TW202140485A - Compounds and uses thereof - Google Patents

Abstract

The present disclosure features compounds useful for the treatment of BAF complex-related disorders.

Description

Compound and its use

The disease may be affected by the BAF complex. BRD9 is a component of BAF complex. The present invention relates to useful compositions and methods for treating BAF complex-related diseases, such as cancer and infections.

Bromodomain-containing protein 9 (BRD9) is a protein encoded by the BRD9 gene on chromosome 5. BRD9 is a component of BAF (BRG1 or BRM-related factor) complex (a SWI/SNF ATPase chromatin remodeling complex), and belongs to the IV family of bromodomain-containing proteins. BRD9 is present in several SWI/SNF ATPase chromatin remodeling complexes and is up-regulated in a variety of cancer cell lines. Therefore, agents that lower the level and/or activity of BRD9 can provide new methods for treating diseases and disorders such as cancer and infections. The inventors have found that depletion of BRD9 in cells causes depletion of SS18-SSX fusion protein in their cells. The SS18-SSX fusion protein is detected in more than 95% of synovial sarcoma tumors, and is usually the only cytogenetic abnormality in synovial sarcoma. In addition, there is evidence that BAF complexes are related to cellular antiviral activity. Therefore, agents (such as compounds) that degrade BRD9 can be used to treat diseases (such as cancer or infection) associated with BAF, BRD9 and/or SS18-SSX.

The present disclosure features compounds and methods that can be used to treat BAF-related disorders, such as cancer or infection.

In one aspect, the present invention features a compound having the structure of any one of compounds D1, S-D1, R-D1, and D2 in Table 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of Compound D1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of compound S-D1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of compound R-D1, or is a pharmaceutically acceptable salt thereof. In other embodiments, the compound has the structure of compound D2, or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention is characterized by a compound having the structure of compound D1 in Table 1, or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention features a compound having the structure of compound S-D1 in Table 1, or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention is characterized by a compound having the structure of compound R-D1 in Table 1, or a pharmaceutically acceptable salt thereof.

S-D1

R-D1

D2

In another aspect, the present invention features a compound having the structure of compound D2 in Table 1, or a pharmaceutically acceptable salt thereof. Table 1. Compounds of the invention Compound number structure D1

S-D1

R-D1

D2

In another aspect, the present disclosure features a pharmaceutical composition comprising any one of the above-mentioned compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In one aspect, the present disclosure features a method of inhibiting the level and/or activity of BRD9 in a cell, the method comprising bringing the cell to an effective amount of any of the above-mentioned compounds or is pharmaceutically acceptable Contact with the salt or its pharmaceutical composition.

In another aspect, the present disclosure features a method for reducing the level and/or activity of BRD9 in a cell, the method comprising bringing the cell to an effective amount of any of the above-mentioned compounds or a pharmaceutically acceptable method. The accepted salt or its pharmaceutical composition is contacted.

In some embodiments, the cell is a cancer cell.

In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colon Rectal cancer, sarcoma (e.g. soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma), osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, fibroproliferative tissue Small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, low Grade rhabdomyosarcoma), non-small cell lung cancer (such as squamous or adenocarcinoma), gastric or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colon Rectal cancer. In some embodiments, the cancer is a sarcoma (such as synovial sarcoma or Ewing's sarcoma), non-small cell lung cancer (such as squamous or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In some embodiments, the sarcoma is a synovial sarcoma.

In one aspect, the present disclosure features a method of treating a BAF complex-related disorder in an individual in need, the method comprising administering to the individual an effective amount of any of the above-mentioned compounds or a pharmaceutically acceptable Accepted salt or its pharmaceutical composition. In some embodiments, the BAF complex related disorder is cancer. In some embodiments, the BAF complex-related disorder is an infection.

In another aspect, the present disclosure features a method for treating an SS18-SSX fusion protein-related disorder in an individual in need, the method comprising administering to the individual an effective amount of any one of the above-mentioned compounds or a medicine thereof Academically acceptable salt or its pharmaceutical composition. In some embodiments, the SS18-SSX fusion protein-related disorder is cancer. In some embodiments, the SS18-SSX fusion protein-related disorder is infection. In some embodiments of any of the foregoing methods, the SS18-SSX fusion protein is SS18-SSX1 fusion protein, SS18-SSX2 fusion protein, or SS18-SSX4 fusion protein.

In another aspect, the present disclosure features a method of treating a BRD9-related disorder in an individual in need, the method comprising administering to the individual an effective amount of any of the above-mentioned compounds or a pharmaceutically acceptable The salt or its pharmaceutical composition. In some embodiments, the BRD9-related disorder is cancer. In some embodiments, the BRD9-related disorder is an infection.

In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck Cancers of the breast, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, especially Burkitt’s lymphoma and non-Hodgkin’s lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangioendothelioma, Kaposi's sarcoma, liposarcoma, sarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendritic glioma, ependymoma , Glioblastoma, Neuroblastoma, Gangliocytoma, Ganglioglioma, Medulloblastoma, Pineal Cell Tumor, Meningioma, Meningiosarcoma, Fibroneuronoma and Schwann Cell Tumor; Intestinal Cancer , Breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodge King's disease, Wilms' tumor and teratoma cancer. Additional cancers that can be treated with the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenal cortex Cancer, anal cancer, degenerative astrocytoma, angiosarcoma, appendix cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem Glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (negative for estrogen, progesterone and HER-2), single negative (estrogen, progesterone) And one of HER-2 negative), estrogen receptor-positive HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal type A breast cancer, luminal type B breast cancer , Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, skin lymphoma, skin melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer , Ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor ( GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer hemangioendothelioma, Hodgkin’s lymphoma, hypopharyngeal carcinoma, invasive ductal carcinoma (IDC), infiltrating Lobular Carcinoma (ILC), Inflammatory Breast Cancer (IBC), Bowel Cancer, Intrahepatic Cholangiocarcinoma, Invasive/Invasive Breast Cancer, Islet Cell Carcinoma, Jaw Cancer, Kaposi's Sarcoma, Kidney Cancer, Laryngeal Cancer, Smooth Muscle Sarcoma, leptomeningeal metastasis, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, Meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal tumor, mesothelioma metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monodermal malformation Fetal tumors, oral cancer colloid carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumors (NET), Non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, eye melanoma, oligodendritic glioma, oral cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, Osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary peritoneal cancer, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, breast cancer Head cancer, sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal tumor, pineal gland Blastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, skeletal sarcoma, sarcoma, sinus cancer , Skin cancer, small cell lung cancer (SCLC), small bowel cancer, spine cancer, spine cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T cell lymphoma, testicular cancer, throat cancer, thymoma/thymic cancer , Thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular cancer, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T cell lineage acute Lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma Tumor, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myeloid monocytic leukemia (JMML), acute promyelocytic leukemia (AML) Subtype), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosal-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, nodular marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis ; B-cell prolymphocytic leukemia; unclassified splenic lymphoma/leukemia, splenic diffuse red marrow small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disease (such as alpha heavy chain disease, gamma heavy chain disease, μ Heavy chain disease), plasma cell myeloma, bone solitary plasma cell sarcoma; extraosseous plasma cell tumor; primary skin follicular center lymphoma, large B-cell lymphoma rich in T cells/histiocytosis, and chronic inflammation Related DLBCL; Elderly Epstein-Barr virus (EBV) + DLBCL; Primary mediastinal (thymus) large B cell lymphoma, primary skin DLBCL, leg type, ALK + large B cell lymphoma Tumor, plasmablastic lymphoma; large B-cell lymphoma that occurs in HHV8-related multicentric Castleman disease; unclassified B with characteristics that are between diffuse large B-cell lymphoma Cell lymphoma, or unclassified B-cell lymphoma with features between diffuse large B-cell lymphoma and classic Hodgkin’s lymphoma.

In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colon Rectal cancer, sarcoma (e.g. soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma), osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, fibroproliferative tissue Small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, low Grade rhabdomyosarcoma), non-small cell lung cancer (such as squamous or adenocarcinoma), gastric or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colon Rectal cancer. In some embodiments, the cancer is a sarcoma (such as synovial sarcoma or Ewing's sarcoma), non-small cell lung cancer (such as squamous or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In some embodiments, the sarcoma is a synovial sarcoma.

In some embodiments, the infection is a viral infection (e.g., the following viral infections: Retroviridae, such as lentiviruses (e.g., human immunodeficiency virus (HIV)) and delta retroviruses (e.g., human T cell leukemia virus (HTLV) -I), human T-cell leukemia virus II (HTLV-II)); Hepadnaviridae (such as hepatitis B virus (HBV)); Flaviviridae (such as hepatitis C virus) (HCV)); Adenoviridae (e.g., human adenovirus); Herpesviridae (e.g., human cytomegalovirus (HCMV), Estein-Barr virus, herpes simplex virus 1 (HSV-1) , Herpes simplex virus 2 (HSV-2), human herpes virus 6 (HHV-6), herpes virus K*, CMV, varicella-zoster virus); Papillomaviridae (such as human papillomavirus ( HPV, HPV E1)); Parvoviridae (e.g. Parvovirus B19); Polyomaviridae (e.g. JC virus and BK virus); Paramyxoviridae (e.g. measles virus); or Togaviridae (such as rubella virus). In some embodiments, the disease is Coffin Siris, neurofibromas (such as NF-1, NF-2, or Schwannomatosis). )) or multiple meningioma. In one aspect, the present disclosure features a method of treating cancer in an individual in need, the method comprising administering to the individual an effective amount of any of the above-mentioned compounds or A pharmaceutically acceptable salt or any of the above-mentioned pharmaceutical compositions.

In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck Cancers of the breast, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, especially Burkitt’s lymphoma and non-Hodgkin’s lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangioendothelioma, Kaposi's sarcoma, liposarcoma, sarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendritic glioma, ependymoma , Glioblastoma, Neuroblastoma, Gangliocytoma, Ganglioglioma, Medulloblastoma, Pineal Cell Tumor, Meningioma, Meningiosarcoma, Fibroneuronoma and Schwann Cell Tumor; Intestinal Cancer , Breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodge King's disease, Wilms' tumor and teratoma cancer. Additional cancers that can be treated with the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenal cortex Cancer, anal cancer, degenerative astrocytoma, angiosarcoma, appendix cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem Glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (negative for estrogen, progesterone and HER-2), single negative (estrogen, progesterone) And one of HER-2 negative), estrogen receptor-positive HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal type A breast cancer, luminal type B breast cancer , Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, skin lymphoma, skin melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer , Ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor ( GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer hemangioendothelioma, Hodgkin’s lymphoma, hypopharyngeal carcinoma, invasive ductal carcinoma (IDC), infiltrating Lobular Carcinoma (ILC), Inflammatory Breast Cancer (IBC), Bowel Cancer, Intrahepatic Cholangiocarcinoma, Invasive/Invasive Breast Cancer, Islet Cell Carcinoma, Jaw Cancer, Kaposi's Sarcoma, Kidney Cancer, Laryngeal Cancer, Smooth Muscle Sarcoma, leptomeningeal metastasis, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, Meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal tumor, mesothelioma metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monodermal malformation Fetal tumors, oral cancer colloid carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumors (NET), Non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, eye melanoma, oligodendritic glioma, oral cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, Osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary peritoneal cancer, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, breast cancer Head cancer, sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal tumor, pineal gland Blastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, skeletal sarcoma, sarcoma, sinus cancer , Skin cancer, small cell lung cancer (SCLC), small bowel cancer, spine cancer, spine cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T cell lymphoma, testicular cancer, throat cancer, thymoma/thymic cancer , Thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular cancer, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T cell lineage acute Lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma Tumor, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myeloid monocytic leukemia (JMML), acute promyelocytic leukemia (AML) Subtype), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosal-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, nodular marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis ; B-cell prolymphocytic leukemia; unclassified splenic lymphoma/leukemia, splenic diffuse red marrow small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disease (such as alpha heavy chain disease, gamma heavy chain disease, μ Heavy chain disease), plasma cell myeloma, bone solitary plasma cell sarcoma; extraosseous plasma cell tumor; primary skin follicular center lymphoma, large B-cell lymphoma rich in T cells/histiocytosis, and chronic inflammation Related DLBCL; Elderly Epstein-Barr virus (EBV) + DLBCL; Primary mediastinal (thymus) large B cell lymphoma, primary skin DLBCL, leg type, ALK + large B cell lymphoma Tumor, plasmablastic lymphoma; large B-cell lymphoma that occurs in HHV8-related multicentric Castleman disease; unclassified B with characteristics that are between diffuse large B-cell lymphoma Cell lymphoma, or unclassified B-cell lymphoma with features between diffuse large B-cell lymphoma and classic Hodgkin’s lymphoma.

In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colon Rectal cancer, sarcoma (e.g. soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma), osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, fibroproliferative tissue Small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, low Grade rhabdomyosarcoma), non-small cell lung cancer (such as squamous or adenocarcinoma), gastric or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colon Rectal cancer. In some embodiments, the cancer is a sarcoma (such as synovial sarcoma or Ewing's sarcoma), non-small cell lung cancer (such as squamous or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In some embodiments, the sarcoma is a synovial sarcoma.

In another aspect, the present disclosure features a method for treating viral infections in individuals in need. This method includes administering to the subject an effective amount of any of the aforementioned compounds, or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is the following viral infections: Retroviral family, such as lentivirus (such as human immunodeficiency virus (HIV) and delta retrovirus (such as human T-cell leukemia virus (HTLV-I), human T Cellular Leukemia Virus II (HTLV-II)); liver deoxyribonucleic acid virus family (e.g. hepatitis B virus (HBV)), flaviviridae (e.g. hepatitis C virus (HCV)), adenoviral family (e.g. human adenovirus) Virus), herpesvirus family (e.g. human cytomegalovirus (HCMV), estane-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpes virus 6 (HHV- 6), herpesvirus K*, CMV, varicella-zoster virus), papillomavirus family (e.g. human papillomavirus (HPV, HPV E1)), parvovirus family (e.g. parvovirus B19), polyomavirus family (Such as JC virus and BK virus), Paramyxoviridae (such as measles virus), Togaviridae (such as rubella virus).

In another embodiment of any of the above methods, the method further comprises administering to the individual an additional anti-cancer therapy (e.g., a chemotherapeutic agent or a cytotoxic agent or radiation therapy).

In certain embodiments, additional anti-cancer therapies are: chemotherapeutic agents or cytotoxic agents (such as doxorubicin or ifosfamide), differentiation-inducing agents (such as retinoic acid, vitamin D. Cytokines), hormonal agents, immunological agents or anti-angiogenesis agents. Chemotherapeutic agents and cytotoxic agents include (but are not limited to) alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposide and other agents (e.g. paclitaxel (paclitaxel), paclitaxel ( taxol), docetaxel, taxotere, cis-platinum). A list of other compounds with anticancer activity can be found in L. Brunton, B. Chabner and B. Knollman (Editor). Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition, 2011, McGraw Hill Companies, New York, NY .

In a specific embodiment, the compound of the present invention and the other anticancer therapy and any of the above-mentioned compounds or pharmaceutical compositions each other within 28 days (e.g., 21 days, 14 days, 10 days, 7 days, 5 days). , 4 days, 3 days, 2 days, or 1 day) or within 24 hours (for example, 12 hours, 6 hours, 3 hours, 2 hours, or 1 hour; or concomitantly), each in an amount effective to treat the individual together. Chemical term

The compounds described herein may have one or more asymmetric carbon atoms and may be optically pure enantiomers, mixtures of enantiomers (such as racemates), optically pure diastereomers, Exist in the form of mixtures of diastereomers, racemates of diastereomers, or mixtures of racemates of diastereomers. The optically active form can be obtained, for example, by resolving racemates, by asymmetric synthesis or asymmetric chromatography (chromatography using a palmar adsorbent or eluent). That is, some of the disclosed compounds can exist in multiple stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers with non-superimposable mirror images, most commonly because they contain asymmetrically substituted carbon atoms used as the opposite center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereoisomers are stereoisomers that are not related to mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent substituents around one or more opposing carbon atoms configuration. The enantiomers of a compound can be prepared, for example, by separating the enantiomers from the racemates by using one or more well-known techniques and methods, such as palm chromatography and separation methods based thereon. Techniques and/or methods suitable for separating the enantiomers of the compounds described herein from racemic mixtures can be easily determined by those skilled in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, where such a mixture does not exhibit optical activity; that is, it does not rotate the plane of polarized light. "Geometric isomers" means isomers that differ in the direction of the substituent atoms associated with the carbon-carbon double bond, cycloalkyl ring, or bridged bicyclic ring system. The atoms on each side of the carbon-carbon double bond (except H) can be in E (substituents are on the opposite side of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis" and "trans" indicate the configuration relative to the core molecule. Some of the disclosed compounds may exist in the form of atropisomers. Atropisomers are stereoisomers caused by hindered rotation around a single bond, where the steric resistance to rotation is high enough to allow separation of conformational isomers. The compounds described herein can be synthesized into individual isomers by isomer-specific synthesis, or resolved from a mixture of isomers. Conventional analysis techniques include the use of optically active acids to form the free base salt of each isomer of the isomer pair (following fractional crystallization and free base regeneration), and the use of optically active amines to form the acid of each isomer of the isomer pair Form salt (following fractional crystallization and free acid regeneration), using optically pure acids, amines or alcohols to form esters or amides of each isomer of the isomer pair (following chromatographic separation and removal of the opposing additives ), or use a variety of well-known chromatographic methods to resolve the isomer mixture of the starting material or the final product. When the stereochemistry of the disclosed compound is named or depicted by the structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% by weight relative to other stereoisomers. % Or 99.9%. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. When a single diastereomer is named or depicted by the structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight . The optical purity percentage is the ratio of the weight of the enantiomer to the weight of the enantiomer plus the weight of the optical isomer. The purity of diastereomers by weight is the ratio of the weight of one diastereomer to all diastereomers. When the stereochemistry of the disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90% relative to other stereoisomers in terms of mole fraction , 99% or 99.9% pure. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in terms of mole fraction . When a single diastereomer is named or depicted by the structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9 in terms of mole fraction %pure. The purity percentage in terms of mole fraction is the ratio of the mole number of the enantiomer to the mole number of the enantiomer plus the mole number of its optical isomer. Similarly, the purity percentage in mole fraction is the ratio of the mole number of the diastereomer to the mole number of the diastereomer plus the mole number of its isomer. When the compound is named or depicted by the structure without indicating stereochemistry and the compound has at least one center of contrast, it should be understood that the name or structure encompasses the enantiomers of the compound that does not contain the corresponding optical isomer , A racemic mixture of a compound or a mixture of an enantiomer that is enriched relative to the corresponding optical isomer. When the compound is named or depicted by the structure without indicating stereochemistry and the compound has two or more opposite centers, it should be understood that the name or structure encompasses non-diastereomers without other diastereomers. Enantiomers, many diastereomers that do not contain other diastereomeric pairs, mixtures of diastereoisomers, mixtures of diastereomeric pairs, one diastereomer A mixture of diastereoisomers or one or more diastereomers relative to other diastereoisomers enriched in diastereomers mixture. The present invention covers all such forms.

The compounds of the present disclosure also include all isotopes of atoms present in the intermediate or final compound. "Isotopes" refer to atoms with the same atomic number but different mass numbers due to the different number of neutrons in the nucleus. For example, hydrogen isotopes include tritium and deuterium.

Unless otherwise stated, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, phosphorus, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N , ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I. Isotope-labeled compounds (for example, compounds labeled with ³ H and ¹⁴ C) can be used in the analysis of compound or substrate tissue distribution. Tritiated (ie ³ H) and carbon 14 (ie ¹⁴ C) isotopes are useful because of their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (ie ² H) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are ^{replaced by 2} H or ³ H, or one or more carbon atoms are ^{replaced by 13} C or ¹⁴ C enriched carbon. Positron emission isotopes such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F can be used in positron emission tomography (PET) studies to check the occupancy of host receptors. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically-labeled compounds can generally be prepared by using isotopically-labeled reagents instead of non-isotopically-labeled reagents according to a formula similar to that disclosed for the compounds of the invention described herein.

As is known in the art, many chemical entities can take many different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including in any solid form. In some embodiments, the compounds described or depicted herein may be provided or utilized in the form of hydrates or solvates.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs. The methods and materials used in this disclosure are described herein; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned in this article are incorporated into this article by reference in their entirety. In case of conflict, this specification including definitions will prevail. definition

In this application, unless otherwise clear from the context, (i) the term "a" can be understood to mean "at least one"; (ii) the term "or" can be understood to mean "and/or"; and (iii) ) The term "comprising" can be understood to encompass the detailed enumerated components or steps, whether presented alone or with the same or multiple additional components or steps.

As used herein, the terms "about" and "approximately" refer to values within 10% higher or lower than the stated value. For example, the term "about 5 nM" indicates a range of 4.5 to 5.5 nM.

As used herein, the term "administration" refers to an individual or system administering a composition (e.g., a compound as described herein or a formulation that includes a compound as described herein). It can be administered to individual animals (such as humans) by any appropriate means. For example, in some embodiments, administration can be via bronchial (including via bronchial perfusion), buccal, intestinal, interdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, Intranasal, intraperitoneal, intrathecal, intratumor, intravenous, intraventricular, transmucosal, transnasal, oral, transrectal, subcutaneous, sublingual, surface, transtracheal (including by intratracheal infusion), percutaneous , Transvaginal and transvitreous.

As used herein, the term "adult soft tissue sarcoma" refers to adolescent and adult individuals (e.g. at least 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, 18 years old, or 19 years old). (Individual) sarcoma appearing in the soft tissues of the body. Non-limiting examples of adult soft tissue sarcoma include (but are not limited to) synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, leiomyosarcoma, hemangioendothelioma, Kaposi's sarcoma, lymphangiosarcoma , Malignant peripheral nerve sheath tumors/neurofibrosarcoma, extraosseous chondrosarcoma, extraosseous osteosarcoma, extraosseous mucoid chondrosarcoma and extraosseous mesenchymal chondrosarcoma.

As used herein, the term "BAF complex" refers to the BRG1 or HRBM-related factor complex in human cells.

As used herein, the term "BAF complex-related disorder" refers to a disorder caused by or affected by the level and/or activity of the BAF complex.

As used herein, the terms "GBAF complex" and "GBAF" refer to the SWI/SNF ATPase chromatin remodeling complex in human cells. The GBAF complex subunits may include, but are not limited to, ACTB, ACTL6A, ACTL6B, BICRA, BICRAL, BRD9, SMARCA2, SMARCA4, SMARCC1, SMARCD1, SMARCD2, SMARCD3, and SS18. The term "cancer" refers to diseases caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias and lymphomas.

As used herein, the term "BRD9" refers to the bromine-containing domain protein 9, a component of BAF (BRG1 or BRM-related factor) complex (a SWI/SNF ATPase chromatin remodeling complex), and belongs to the bromine-containing structure The IV family of domain proteins. BRD9 is encoded by the BRD9 gene, and its nucleic acid sequence is shown in SEQ ID NO:1. The term "BRD9" also refers to a natural variant of the wild-type BRD9 protein, such as the protein having at least 85% sequence identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% consistency or more).

As used herein, the term "BRD9-related disorder" refers to a disorder caused by or affected by the level and/or activity of BRD9. The term "cancer" refers to diseases caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias and lymphomas.

As used herein, "combination therapy" or "combination administration" means that two (or more) different agents or treatments are administered to an individual as part of a treatment regimen defined for a particular disease or condition. The treatment plan defines the dosage and period of each agent, so that the effects of the individual agents on the individual overlap. In some embodiments, the delivery of two or more agents is simultaneous or simultaneous, and the agents can be formulated together. In some embodiments, the two or more agents are not co-formulated and are administered in a continuous manner as part of a designated regimen. In some embodiments, the administration of two or more agents or treatments in combination results in a reduction in symptoms or other parameters related to the condition to a degree that exceeds what would be observed under one agent or treatment delivered alone or in the absence of other agents or treatments. Symptoms or parameters. The effects of the two treatments can be partially cumulative, overall cumulative, or more than cumulative (for example, synergy). The continuous or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route, including (but not limited to) oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissues. The therapeutic agents can be administered by the same route or by different routes. For example, the combined therapeutic agent can be administered by intravenous injection, and the combined second therapeutic agent can be administered orally.

As used herein, "the compound of the present invention" and similar terms, whether or not explicitly indicated, refer to compounds that can be used to treat the BAF-related disorders (such as cancer or infection) described herein, such as compound D1, compound S-D1, and Compound R-D1 or Compound D2, and its salts (for example, pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers) and tautomers. Those skilled in the art will understand that certain compounds described herein can be in one or more different isomers (such as stereoisomers, geometric isomers, atropisomers, and tautomers) or isotopes ( For example, one or more atoms have been substituted with different isotopes of the atom, such as deuterium instead of hydrogen). Unless otherwise indicated or clear from the context, the depicted structures can be understood to represent any such isomeric or isotopic forms individually or in combination. The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers such as enantiomers and diastereomers are intended. The compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and their analogs can also be present in the compounds described herein, and this disclosure encompasses all such stable isomers. The cis and trans geometric isomers of the compounds described in the present disclosure can be separated as a mixture of isomers or as individual isomers. In some embodiments, one or more of the compounds described herein may exist in different tautomeric forms. If it is clear from the context, references to such compounds encompass all such tautomeric forms unless explicitly excluded. In some embodiments, tautomeric forms result from the exchange of single bonds with adjacent double bonds and accompanying proton migration. In some embodiments, the tautomeric form may be a proton shift tautomer, which is the protonation state of an isomeric substance having the same empirical formula and total charge as the reference form. Examples of moieties with proton shift tautomeric forms are keto-enol pairs, amide-imine pairs, endo-amino-imine pairs, enamine-imine pairs, enamine-imine pairs For cyclic forms, where protons can occupy two or more positions in the heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, the tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion.

As used herein, the term "degrading agent" refers to a small molecule compound that includes a degraded portion, where the compound interacts with a protein (such as BRD9) in a manner that causes protein degradation, for example, the binding of the compound causes, for example, a decrease in protein levels in cells or individuals At least 5%.

As used herein, the term "degradation moiety" refers to a moiety that binds to cause protein degradation such as BRD9. In one example, the moiety binds to a protease or ubiquitin ligase that metabolizes proteins such as BRD9.

"Determining protein levels" means directly or indirectly detecting proteins or mRNA encoding proteins by methods known in the art. "Direct determination" means performing a method (eg, performing analysis or testing on a sample or "analyzing a sample" as the term is defined herein) to obtain a physical entity or value. "Indirect measurement" refers to receiving a physical entity or value from another party or source (for example, a third-party laboratory that directly obtains the physical entity or value). Methods of measuring protein levels generally include (but are not limited to) Western blotting method, immunoblotting method, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasma Resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microflow cytometry Techniques, microscopy, fluorescence-activated cell sorting (FACS) and flow cytometry, as well as analysis based on protein properties including (but not limited to) enzyme activity or interaction with other protein partners. Methods for measuring mRNA levels are known in the art.

As used herein, the term "effective amount", "therapeutically effective amount" and "sufficient amount" of an agent that reduces the level and/or activity of BRD9 (for example, in cells or individuals) as described herein refers to individuals including humans The amount sufficient to achieve beneficial or desired results at the time of administration, including clinical results, therefore, "effective amount" or its synonyms depend on the context of its application. For example, in the context of the treatment of cancer, it is an amount sufficient to achieve a therapeutic response compared to the response obtained without administration of an agent that reduces the level and/or activity of BRD9 . The amount of a given agent that reduces the level and/or activity of BRD9 as described herein corresponding to such an amount will vary depending on a variety of factors, such as the given agent, pharmaceutical preparation, route of administration, disease or The type of disease, the characteristics of the individual or host being treated (for example, age, sex, and/or weight) and similar factors can be routinely determined by those skilled in the art. In addition, as used herein, the "therapeutically effective amount" of the agent that reduces the level and/or activity of BRD9 in the present disclosure is the amount that produces a beneficial or desired result in an individual compared to a control. As defined herein, the therapeutically effective amount of the agent for reducing the level and/or activity of BRD9 in the present disclosure can be easily determined by a person of ordinary skill in the art by conventional methods known in the art. The dosage regimen can be adjusted to provide the best therapeutic response.

As used herein, the term "inhibitor" refers to any agent that reduces the level and/or activity of a protein (such as BRD9). Non-limiting examples of inhibitors include small molecule inhibitors, degradants, antibodies, enzymes, or polynucleotides (e.g., siRNA).

"Level" means the level of the protein or mRNA encoding the protein compared to the reference. The reference can be any useful reference as defined herein. The "decrease level" or "increase level" of the protein means that the protein level is decreased or increased compared to the reference (e.g. decreased or increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30% , About 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; compared with the reference, decrease or increase by more than about 10%, about 15%, about 20%, About 50%, about 75%, about 100%, or about 200%; decrease or increase by less than about 0.01 times, about 0.02 times, about 0.1 times, about 0.3 times, about 0.5 times, about 0.8 times or less; or increase by more than About 1.2 times, about 1.4 times, about 1.5 times, about 1.8 times, about 2.0 times, about 3.0 times, about 3.5 times, about 4.5 times, about 5.0 times, about 10 times, about 15 times, about 20 times, about 30 times Times, about 40 times, about 50 times, about 100 times, about 1000 times or more). The protein level can be expressed relative to the quality/volume (eg g/dL, mg/mL, μg/mL, ng/mL) or percentage of the total protein or mRNA in the sample.

"Regulating the activity of the BAF complex" means to change the level of the activity related to the BAF complex (such as GBAF), or related downstream effects. The activity level of the BAF complex can be measured using any method known in the art, for example, the method described in Kadoch et al., Cell 153:71-85 (2013), and these methods are incorporated herein by reference.

The "percentage of sequence identity (%)" with respect to a reference polynucleotide or polypeptide sequence is defined as the comparison between the candidate sequence and the reference polynucleotide or polypeptide sequence after the sequence is aligned and gaps are introduced when necessary to achieve the maximum sequence identity percentage. The percentage of the nucleic acid or amino acid that is the same as the nucleic acid or amino acid. The alignment used to determine the percent identity of nucleic acid or amino acid sequences can be implemented in a variety of ways within the capabilities of those skilled in the art, for example, using publicly available computer software, such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine the appropriate parameters for the alignment of the sequences, including any algorithms required to achieve the maximum alignment over the full-length sequences being compared. For example, the sequence comparison computer program BLAST can be used to generate a sequence identity percentage value. As an illustration, the percentage of sequence identity of a given nucleic acid or amino acid sequence A relative to, with or compared to a given nucleic acid or amino acid sequence B (which can alternatively be expressed as relative to, and or compared with The given nucleic acid or amino acid sequence B has a certain percentage of sequence identity A) is calculated as follows: Multiply by 100 (fraction X/Y) Where X is the number of nucleotides or amino acids that are scored as unanimous matches in sequence comparison programs (such as BLAST) for comparing A and B, and Y is the total number of nucleic acids in B. It should be understood that when the length of the nucleic acid or amino acid sequence A is not equal to the length of the nucleic acid or amino acid sequence B, the sequence identity percentage of A to B is not equal to the sequence identity percentage of B to A.

As used herein, "pharmaceutically acceptable excipients" refer to compounds other than the compounds described herein (e.g., vehicles capable of suspending or dissolving the active compound) and that are substantially non-toxic and non-inflammatory in patients Characteristics of any ingredients. Excipients may include, for example: anti-adhesive agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film forming agents Or coatings, flavoring agents, perfumes, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners and hydration water.

As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of any of the compounds described herein. For example, pharmaceutically acceptable salts of any compound described herein are included within the scope of reasonable medical judgment, suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, and allergic reactions, and with reasonable benefits /Risk ratio commensurate with salt. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in the following: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (edited by PH Stahl and CG Wermuth) , Wiley-VCH, 2008. Salts can be prepared on the spot during the final isolation and purification of the compounds described herein, or separately prepared by reacting the free base group with a suitable organic acid. The compounds described herein may have ionizable groups so that they can be prepared into pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or in the case of the acidic forms of the compounds described herein, the salts may be prepared from inorganic or organic bases. The compound is often prepared as a pharmaceutically acceptable salt prepared as a pharmaceutically acceptable acid or base addition product or used as a pharmaceutically acceptable salt. The preparation methods of suitable pharmaceutically acceptable acids and bases and suitable salts are well known in the art. Salts can be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic acids and organic acids, as well as inorganic bases and organic bases.

As used herein, the term "pharmaceutical composition" means that it contains the compound described herein formulated with pharmaceutically acceptable excipients and is manufactured as part of a treatment plan for the treatment of diseases in mammals approved by a government regulatory agency Or the composition sold. The pharmaceutical composition can, for example, be formulated for oral administration in a unit dosage form (for example, lozenge, capsule, caplet, gelatin capsule or syrup); for topical administration (for example, as a cream, gel, lotion or ointment); for Intravenous administration (for example, as a sterile solution that does not contain microscopic emboli and is suitable for intravenous use in a solvent system); or in any other pharmaceutically acceptable formulation.

"Reduce BRD9 activity" means to reduce the level of BRD9-related activity or related downstream effects. One non-limiting example of inhibiting BRD9 activity is reducing the level of BAF complexes (e.g. GBAF) in cells. The activity level of BRD9 can be measured using any method known in the art. In some embodiments, the agent that reduces the activity of BRD9 is a small molecule BRD9 inhibitor. In some embodiments, the agent that reduces the activity of BRD9 is a small molecule BRD9 degrading agent.

"Reduce the level of BRD9" means to reduce the level of BRD9 in a cell or an individual. The level of BRD9 can be measured using any method known in the art.

"Reference" means any useful reference for comparing protein or mRNA levels. The reference can be any sample, standard, standard curve or level used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. The "reference sample" can be, for example, a control, such as a predetermined negative control value, such as a "normal control" taken from the same individual or a previous sample; a sample from a normal healthy individual, such as normal cells or normal tissue; A sample of a diseased individual (such as a cell or tissue); a sample from an individual diagnosed with a disease but not treated with a compound described herein; a sample from an individual that has been treated with a compound described herein; or a sample that has been purified Know a sample of the protein (such as any one described herein) at a standard concentration. "Reference standard or level" means a value or value derived from a reference sample. "Normal control value" is a predictive value indicating a non-disease condition, such as a value expected in healthy control individuals. Generally, the normal control value can be expressed as a range ("between X and Y"), a high threshold ("not higher than X"), or a low threshold ("not lower than X"). An individual whose measured value for a specific biomarker is within the normal control value is usually said to be within the "normal limits" of the biomarker. The normal reference standard or level may be a value or value derived from a normal individual who does not have a disease or condition (such as cancer); an individual who has been treated with the compounds described herein. In a preferred embodiment, the reference sample, standard or level is matched with the sample tested sample by at least one of the following criteria: age, weight, gender, disease stage, and general health status. The purified protein within the normal reference range, such as a standard curve of any of the levels described herein, can also be used as a reference.

As used herein, the term "individual" refers to any organism to which the composition according to the present invention can be administered, for example, for experimental, diagnostic, prophylactic and/or therapeutic purposes. Typical individuals include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). Individuals may seek or need treatment, need treatment, are undergoing treatment, will be treated in the future, or be a human or animal under the care of a well-trained professional for a specific disease or condition.

As used herein, the term "SS18-SSX fusion protein-related disorder" refers to a disorder caused by or affected by the level and/or activity of the SS18-SSX fusion protein.

As used herein, the term "treat/treated/treating" means therapeutic treatment and preventive or preventive measures, in which the goal is to prevent or slow down (relieve) undesirable physiological disorders, disorders or diseases, or obtain Beneficial or expected clinical results. Beneficial or desired clinical results include (but are not limited to) alleviation of symptoms; reduction of the severity of the disease, disease, or disease; stable state of the disease, disease, or disease (that is, no deterioration); delayed or slower onset of disease, disease, or disease progression ; Improve disease, disease or disease condition or symptom relief (whether partly or overall), whether detectable or undetectable; improve at least one measurable physical parameter, which may not be discernible by the patient; or improve disease, disease or disease Or get better. Treatment involves causing clinically significant reactions without excessive side effects. Treatment also includes prolonging survival compared to expected survival without receiving treatment.

As used herein, the terms "variant" and "derivative" are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogs of the compounds, peptides, proteins, or other substances described herein. The variants or derivatives of the compounds, peptides, proteins or other substances described herein can retain or improve the biological activity of the original substances.

The details of one or more embodiments of the present invention are set forth in the following description. Other features, objects and advantages of the present invention will be apparent from the description and the scope of the patent application.

The present disclosure features compositions and methods that can be used to treat BAF-related disorders, such as cancer and infection. The present disclosure is further characterized by compositions and methods that can be used to inhibit the level and/or activity of BRD9 in individuals in need, for example, for the treatment of conditions such as cancer (e.g., sarcoma) and infection (e.g., viral infection). Compound

The compounds described herein reduce the level of BRD9-related activity or related downstream effects in a cell or individual, or reduce the level of BRD9 in a cell or individual. The exemplary compounds described herein have the structures of compounds D1, S-D1, R-D1 and D2 in Table 1, or pharmaceutically acceptable salts thereof. Medical use

The compounds described herein can be used in the methods of the present invention, and although not bound by theory, it is believed that they can regulate the level, state, and/or activity of BAF complexes, for example, by inhibiting cells in mammals. The activity or level of the BRD9 protein in the BAF complex plays its ideal role.

One aspect of the present invention relates to methods for treating BRD9-related conditions, such as cancer in individuals in need. In some embodiments, the compound is administered in an amount and time effective to produce one of the following (or more, such as two or more, three or more, four or more) : (A) reduce tumor size; (b) reduce tumor growth rate; (c) increase tumor cell death; (d) slow down tumor progression; (e) reduce the number of metastases; (f) reduce metastasis rate; (g) Reduce tumor recurrence; (h) increase the survival rate of the individual; and (i) increase the progression-free survival of the individual.

Treating cancer can cause tumor size or volume to decrease. For example, after treatment, the size of the tumor is reduced by 5% or more relative to its size before treatment (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% , 90% or greater). The tumor size can be measured by any reproducible measurement method. For example, tumor size can be measured as tumor diameter.

Treating cancer can further reduce the number of tumors. For example, after treatment, the number of tumors is reduced by 5% or more relative to the number before treatment (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%). % Or greater). The number of tumors can be measured by any reproducible measurement method. For example, the number of tumors can be measured by counting tumors that are visible to the naked eye or at a specified magnification (such as 2x, 3x, 4x, 5x, 10x, or 50x) .

Treatment of cancer can cause a decrease in the number of metastatic nodules in other tissues or organs far away from the original tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or more relative to the number before treatment (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%). %, 90% or greater). The number of metastatic nodules can be measured by any reproducible measurement method. For example, the number of metastatic nodules can be measured by counting the metastatic nodules visible to the naked eye or at a specified magnification (for example, 2x, 10x, or 50x).

Treating cancer can cause an increase in the average survival time of a population of individuals treated according to the present invention compared to a population of untreated individuals. For example, the average survival time increases by more than 30 days (more than 60 days, 90 days, or 120 days). The increase in the average survival time of the population can be measured by any reproducible method. The increase in the average survival time of the population can be measured, for example, by calculating the average survival time of the population after starting treatment with the compounds described herein. The increase in the average survival time of a population can also be measured, for example, by calculating the average survival time of the population after the first round of treatment with a pharmaceutically acceptable salt of the compound described herein.

Treating cancer can also cause a decrease in the mortality rate of the population of treated individuals compared to the untreated population. For example, the death rate decreased by more than 2% (e.g., more than 5%, 10%, or 25%). The reduction in mortality of the population of individuals to be treated can be measured by any reproducible method, for example, by calculating the population’s disease-related deaths per unit time after starting treatment with the pharmaceutically acceptable salts of the compounds described herein The average number is measured. The decrease in mortality in a population can also be measured by calculating the average number of disease-related deaths per unit time after the population has finished the first round of treatment with a pharmaceutically acceptable salt of the compound described herein. Combination therapy

The method of the present invention can be used alone or in combination with another therapeutic agent, such as other agents for the treatment of cancer or cancer-related symptoms, or in combination with other types of therapies for the treatment of cancer. In combination therapy, the dose of one or more of the therapeutic compounds can be reduced from the standard dose when administered alone. For example, the dose can be determined empirically from drug combinations and permutations, or can be derived by isoradiometric analysis (eg, Black et al., Neurology 65:S3-S6 (2005)). In this case, the dosage of the compound when combined will provide a therapeutic effect.

In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other compound that can be used to treat cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topological differences Enzyme inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted urea, methylhydrazine derivatives, adrenal cortex inhibitors, adrenal corticosteroids, progesterone, estrogen, anti-estrogens, androgens, Antiandrogens and gonadotropin releasing hormone analogs. Also includes 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel and polyene Paclitaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piperazine Piposulfan; aziridines, such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimine and methylmelamine , Including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; Polyacetogenin (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; Callistatin (callystatin); CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycin (in particular Nostril 1 and Nostril 8); dolastatin; duocarmycin (including synthetic analogues KW-2189 and CB1-TM1); eleutherobin; water ghost Pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholephosamine (cholophosphamide), estramustine, ifosfamide, mechlorethamine, nitrogen mustard oxide hydrochloride, melphalan, novembichin, benzene Phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorurea (chlorozotocin) , Formustine (fotemustine), lomustine (lomustine), nimustine (nimustine) and ramustine (ranimnustine); antibiotics, such as enediyne antibiotics (for example, calicheamicin), Especially calicheamicin γll and calicheamicin γll (see, for example, Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin (dynemicin), including dynemicin A; double Phosphonates (bisphosphonates, such as clodronate; esperamicin; and new carcinogen chromophores and related chromophores enediyne antibiotic chromophores), Akra Aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin , Caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-heavy Nitrogen-5-oxo-L-ortho-leucine, ADRIAMYCIN® (doxorubicin, including morpholinyl-doxorubicin, cyanomorpholinyl-doxorubicin, 2- Pyrololinyl-doxorubicin and deoxydoxorubicin), epirubicin (epirubicin), esorubicin (esorubicin), idarubicin (idarubicin), marcellomycin (marcellomycin), silk Mitomycin (mitomycin) (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycins, peplomycin, Pofiromycin (potfiromycin), puromycin (puromycin), tri-iron adriamycin (quelamycin), rhodoubicin (rodorubicin), streptomycin (streptonigrin), streptozocin (streptozocin), tuberculosis Tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate (methostatin) trexate) and 5-fluorouracil (5-FU); folate analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fluda Labine (fludarabine), 6-mercaptopurine (6-mercaptopurine), thiamiprine (thiamiprine), thioguanine (thioguanine); pyrimidine analogs, such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine ), floxuridine (floxuridine); androgens, such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testosterone ( testolactone); anti-adrenal drugs, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as frolinic acid; aceglatone ; Aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene ; Edatraxate (edatraxate); Defofamine (defofamine); Demecolcine (demecolcine); Diaziquone (diaziquone); Elfomithine (elfomithine); Elliptinium acetate (elliptinium acetate); Epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine maytansine and ansamitocin; mitoguazone; mitoxantrone; mopid anmol); nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid ); 2-Ethylhydrazine; Procarbazine; PSK® Polysaccharide Complex (JHS Natural Products, Eugene, OR); Razoxane; Rhizoxin; Sizofuran ; Spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes ( Especially T-2 toxin, verracurin A, roridin A and anguidine; urethan; vindesine; dacarbazine (dacarbazine); mannomustine (mannomustine); dibromomannitol (mitobronitol); mitolactol (mitolactol); pipobroman (pipobroman); plus cytosine (gacytosine); arabinoside , "Ara-C");cyclophosphamide;thiotepa; taxoids, such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® without cremophor The albumin engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, IL) and TAXOTERE® docetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (etoposide, VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; tenipo side); edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan ( For example, CPT-11); topoisomerase inhibitor RFS 2000; difluoromethyl]ornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and any of the above A pharmaceutically acceptable salt, acid or derivative. Two or more chemotherapeutic agents may be used as a mixture to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are known in the art and are described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol . 18:233a (1999), and Douillard et al., Lancet 355(9209):1041 -1047 (2000).

In some embodiments, the second therapeutic agent is a DNA damaging agent (eg, platinum-based antitumor agents, topoisomerase inhibitors, PARP inhibitors, alkylating antitumor agents, and ionizing radiation).

Examples of platinum-based antitumor agents that can be used as the second therapeutic agent in the composition and method of the present invention are cisplatin, carboplatin, oxaliplatin, dicycloplatin, eptaplatin, and Platinum (lobaplatin), miriplatin, nedaplatin, triplatin tetranitrate, phenanthrilplatin, picoplatin, and satraplatin. In some embodiments, the second therapeutic agent is cisplatin and the cancer being treated is testicular cancer, ovarian cancer, or bladder cancer (eg, advanced bladder cancer). In some embodiments, the second therapeutic agent is carboplatin and the cancer being treated is ovarian cancer, lung cancer, head and neck cancer, brain cancer, or neuroblastoma. In some embodiments, the second therapeutic agent is oxaliplatin and the cancer treated is colorectal cancer. In some embodiments, the second therapeutic agent is bicycloplatin and the cancer treated is non-small cell lung cancer or prostate cancer. In some embodiments, the second therapeutic agent is etaplatin and the cancer being treated is gastric cancer. In some embodiments, the second therapeutic agent is lobaplatin and the cancer being treated is breast cancer. In some embodiments, the second therapeutic agent is miplatin and the cancer being treated is hepatocellular carcinoma. In some embodiments, the second therapeutic agent is nedaplatin and the cancer treated is nasopharyngeal cancer, esophageal cancer, squamous cell carcinoma, or cervical cancer. In some embodiments, the second therapeutic agent is triplatin tetranitrate and the cancer to be treated is lung cancer (eg, small cell lung cancer) or pancreatic cancer. In some embodiments, the second therapeutic agent is picoplatin and the cancer being treated is lung cancer (eg, small cell lung cancer), prostate cancer, bladder cancer, or colorectal cancer. In some embodiments, the second therapeutic agent is satroplatin and the cancer being treated is prostate cancer, breast cancer, or lung cancer.

Examples of topoisomerase inhibitors that can be used as the second therapeutic agent in the compositions and methods of the present invention are etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, Amsacrine, ellipticine, irinotecan, topotecan, camptothecin and diflomotecan. In some embodiments, the second therapeutic agent is etoposide and the cancer treated is lung cancer (eg, small cell lung cancer) or testicular cancer. In some embodiments, the second therapeutic agent is teniposide and the cancer being treated is acute lymphoblastic leukemia (eg, childhood acute lymphoblastic leukemia). In some embodiments, the second therapeutic agent is doxorubicin and the cancer being treated is acute lymphoblastic leukemia, acute medulloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast cancer , Wilmes’ tumor, neuroblastoma, soft tissue sarcoma, osteosarcoma, ovarian cancer, transitional cell carcinoma of the bladder, thyroid cancer, gastric cancer or bronchial cancer. In some embodiments, the second therapeutic agent is daunorubicin and the cancer being treated is acute lymphoblastic leukemia or acute myelogenous leukemia. In some embodiments, the second therapeutic agent is mitoxantrone and the cancer treated is prostate cancer or acute non-lymphocytic leukemia. In some embodiments, the second therapeutic agent is amsacrine and the cancer being treated is leukemia (e.g., acute adult leukemia). In some embodiments, the second therapeutic agent is irinotecan and the cancer treated is colorectal cancer. In some embodiments, the second therapeutic agent is topotecan and the cancer being treated is lung cancer (eg, small cell lung cancer). In some embodiments, the second therapeutic agent is diflutecan and the cancer being treated is lung cancer (eg, small cell lung cancer).

Examples of alkylated anti-tumor agents that can be used as the second therapeutic agent in the composition and method of the present invention are cyclophosphamide, uracil, melphalan, chlorambucil, and ifosine Amine, bendamustine, carmustine, lomustine, chlorurea, formustine, nimustine, ramustine, busulfan, improsufan, piposul Van, chlorambucil, cholephosphamide, estramustine, chlorambucil, nitric oxide mustard hydrochloride, new enbuxine, phenmustine cholesterol, prednimustine, trifosamine, procarbazine, hexamethyl Melamine, dacarbazine, mitozolomide and temozolomide. In some embodiments, the second therapeutic agent is cyclophosphamide and the cancer treated is non-Hodgkin's lymphoma. In some embodiments, the second therapeutic agent is melphalan and the cancer being treated is multiple myeloma, ovarian cancer, or melanoma. In some embodiments, the second therapeutic agent is chlorambucil and the cancer treated is chronic lymphocytic leukemia, malignant lymphoma (eg, lymphosarcoma, giant follicular lymphoma, or Hodgkin's lymphoma). In some embodiments, the second therapeutic agent is ifosfamide and the cancer treated is testicular cancer. In some embodiments, the second therapeutic agent is bendamustine and the cancer treated is chronic lymphocytic leukemia or non-Hodgkin's lymphoma. In some embodiments, the second therapeutic agent is carmustine and the cancer being treated is brain cancer (e.g., glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, or metastasis Brain tumors), multiple myeloma, Hodgkin’s disease or non-Hodgkin’s lymphoma. In some embodiments, the second therapeutic agent is lomustine and the cancer treated is brain cancer or Hodgkin's lymphoma. In some embodiments, the second therapeutic agent is formustine and the cancer being treated is melanoma. In some embodiments, the second therapeutic agent is nimustine and the cancer being treated is brain cancer. In some embodiments, the second therapeutic agent is ramustine and the cancer being treated is chronic myelogenous leukemia or polycythemia vera. In some embodiments, the second therapeutic agent is busulfan and the cancer being treated is chronic myelogenous leukemia. In some embodiments, the second therapeutic agent is Inprofen and the cancer being treated is sarcoma. In some embodiments, the second therapeutic agent is estramustine and the cancer being treated is prostate cancer (e.g., prostate cancer). In some embodiments, the second therapeutic agent is nitrogen mustard and the cancer treated is cutaneous T-cell lymphoma. In some embodiments, the second therapeutic agent is trifosamide and the cancer being treated is a sarcoma (eg, soft tissue sarcoma). In some embodiments, the second therapeutic agent is procarbazine and the cancer being treated is Hodgkin's disease. In some embodiments, the second therapeutic agent is hexamethylmelamine and the cancer being treated is ovarian cancer. In some embodiments, the second therapeutic agent is dacarbazine and the cancer being treated is melanoma, Hodgkin's lymphoma, or sarcoma. In some embodiments, the second therapeutic agent is temozolomide and the cancer being treated is brain cancer (such as astrocytoma or glioblastoma) or lung cancer (such as small cell lung cancer).

Examples of PARP inhibitors that can be used as the second therapeutic agent in the composition and method of the present invention are niraparib, olaparib, rucaparib, and tatarab Talazoparib, veliparib, pamiparib, CK-102 or E7016. Advantageously, the compound of the present invention and the DNA damaging agent can be used synergistically to treat cancer. In some embodiments, the second therapeutic agent is niraparib and the cancer to be treated is ovarian cancer (e.g., BRCA-mutated ovarian cancer), fallopian tube cancer (e.g., BRCA-mutated fallopian tube cancer), or primary peritoneal cancer (e.g., BRCA Mutation of primary peritoneal cancer). In some embodiments, the second therapeutic agent is olaparib and the cancer to be treated is lung cancer (e.g., small cell lung cancer), ovarian cancer (e.g., BRCA-mutated ovarian cancer), breast cancer (e.g., BRCA-mutated breast cancer), fallopian tube cancer (Such as BRCA mutant fallopian tube cancer), primary peritoneal cancer (such as BRCA mutant primary peritoneal cancer), prostate cancer (such as castration resistant prostate cancer) or pancreatic cancer (such as pancreatic cancer). In some embodiments, the second therapeutic agent is lukapanib and the cancer to be treated is ovarian cancer (e.g., BRCA-mutated ovarian cancer), fallopian tube cancer (e.g., BRCA-mutated fallopian tube cancer), or primary peritoneal cancer (e.g., BRCA Mutation of primary peritoneal cancer). In some embodiments, the second therapeutic agent is Tarazopanib and the cancer being treated is breast cancer (eg, BRCA-mutated breast cancer). In some embodiments, the second therapeutic agent is velipanib and the cancer being treated is lung cancer (e.g., non-small cell lung cancer), melanoma, breast cancer, ovarian cancer, prostate cancer, or brain cancer. In some embodiments, the second therapeutic agent is pamidril and the cancer being treated is ovarian cancer. In some embodiments, the second therapeutic agent is CK-102 and the cancer treated is lung cancer (eg, non-small cell lung cancer). In some embodiments, the second therapeutic agent is E7016 and the cancer being treated is melanoma.

Without wishing to be bound by theory, the synergy between the compound of the present invention and the DNA damaging agent can be attributed to the necessity of BRD9 for DNA repair; BRD9 inhibition can make cancer (such as cancer cells or tissues) sensitive to the DNA damaging agent.

In some embodiments, the second therapeutic agent is a JAK inhibitor (e.g., a JAK1 inhibitor). Non-limiting examples of JAK inhibitors that can be used as the second therapeutic agent in the compositions and methods of the present invention include tofacitinib, ruxolitinib, oclacitinib, and Baricitinib, Peficitinib, Fedratinib, Upadacitinib, Filgotinib, Cerdulatinib, Gandotin Gandotinib, lestatinib, momelotinib, pacritinib, abrocitinib, solcitinib, itacitinib ) Or SHR0302. Without wishing to be bound by theory, the synergy between the compound of the present invention and JAK inhibitor can be an inhibitor of SAGA complex due to its combined effect of down-regulating Foxp3+ Treg cells. In some embodiments, the second therapeutic agent is Rousotinib and the cancer to be treated is a myeloproliferative neoplasm (such as polycythemia or myelofibrosis), ovarian cancer, breast cancer, pancreatic cancer. In some embodiments, the second therapeutic agent is fidetinib and the cancer being treated is a myeloproliferative neoplasm (eg, myelofibrosis). In some embodiments, the second therapeutic agent is sedutinib and the cancer being treated is lymphoma (e.g., peripheral T cell lymphoma). In some embodiments, the second therapeutic agent is gandotinib and the cancer being treated is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis). In some embodiments, the second therapeutic agent is letatinib and the cancer to be treated is a myeloproliferative neoplasm (e.g. polycythemia or myelofibrosis), leukemia (e.g. acute myelogenous leukemia), pancreatic cancer, prostate Carcinoma or neuroblastoma. In some embodiments, the second therapeutic agent is molotinib and the cancer treated is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis) or pancreatic cancer (e.g., pancreatic ductal adenocarcinoma). In some embodiments, the second therapeutic agent is molotinib and the cancer being treated is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis). In some embodiments, the second therapeutic agent is molotinib and the cancer treated is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis) or pancreatic cancer (e.g., pancreatic ductal adenocarcinoma).

In some embodiments, the second therapeutic agent is an inhibitor of the SAGA complex or its components. The SAGA complex inhibitor can be, for example, CCDC101, Tada2B, Tada3, Usp22, Tada1, Taf6l, Supt5, Supt20, or a combination of inhibitory antibodies or small molecule inhibitors. Without wishing to be bound by theory, the synergy between the compound of the present invention and the inhibitor of the SAGA complex can be attributed to its combined effect of down-regulating Foxp3+ Treg cells. In some embodiments, the second therapeutic agent is a therapeutic agent used as a biological agent for cancer treatment, such as a cytokine (e.g., interferon or interleukin (e.g., IL-2)). In some embodiments, the biological agent is an anti-angiogenic agent, such as an anti-VEGF agent, for example, bevacizumab (AVASTIN®). In some embodiments, the biological agent is an immunoglobulin-based biological agent that has a stimulating effect on the target to stimulate an anti-cancer response or antagonize an antigen important to cancer, such as a monoclonal antibody (e.g., a humanized antibody, a complete Human antibodies, Fc fusion proteins or functional fragments thereof). Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab ( palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alenduzumab) (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab) Anti-I-131 (tositumomab-I-131)); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI ® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOLIRIS® (Eculizumab); CIMZIA® (polyethylene glycol-conjugated certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakizumab) Anti (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (Movizumab) Monoclonal antibody (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (Weib Tuximab (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (maytansin trastuzumab) Anti-(ado-trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also includes antibody-drug conjugates.

The second agent may be a therapeutic agent as a non-drug treatment. For example, the second therapeutic agent is radiotherapy, cryotherapy, hyperthermia, and/or surgical resection of tumor tissue.

The second agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody can be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc receptor fusion protein. In some embodiments, checkpoint inhibitors are agents that interact with checkpoint proteins, such as antibodies. In some embodiments, checkpoint inhibitors are agents that interact with ligands of checkpoint proteins, such as antibodies. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA4 antibody or fusion protein, such as ipilimumab/YERVOY® or tremelimumab) . In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor (e.g., inhibitory antibody or small molecule inhibitor) (e.g. nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; pilivizumab/ CT-011). In some embodiments, the checkpoint inhibitor is a PDL1 inhibitor (e.g., inhibitory antibody or small molecule inhibitor) (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the checkpoint inhibitor is a PDL2 inhibitor (e.g., inhibitory antibody or Fc fusion or small molecule inhibitor) (e.g., PDL2/Ig fusion protein, such as AMP 224). In some embodiments, the checkpoint inhibitor is B7-H3 (e.g. MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, Inhibitors of A2aR, B-7 family ligands or combinations thereof (for example, inhibitory antibodies or small molecule inhibitors). In some embodiments, the second therapeutic agent is ipilimumab and the cancer to be treated is melanoma, kidney cancer, lung cancer (eg, non-small cell lung cancer or small cell lung cancer), or prostate cancer. In some embodiments, the second therapeutic agent is tremelizumab and the cancer being treated is melanoma, mesothelioma, or lung cancer (e.g., non-small cell lung cancer). In some embodiments, the second therapeutic agent is nivolumab and the cancer treated is melanoma, lung cancer (e.g. non-small cell lung cancer or small cell lung cancer), kidney cancer, Hodgkin’s lymphoma, head and neck cancer (e.g. Squamous cell carcinoma of the head and neck), urothelial carcinoma, hepatocellular carcinoma or colorectal cancer. In some embodiments, the second therapeutic agent is pembrolizumab and the cancer to be treated is melanoma, lung cancer (such as non-small cell lung cancer or small cell lung cancer), Hodgkin’s lymphoma, head and neck cancer (such as head and neck squamous cell Cell carcinoma), primary mediastinal large B-cell lymphoma, urothelial carcinoma, hepatocellular carcinoma, high microsatellite instability cancer, gastric cancer, esophageal cancer, cervical cancer, Merkel cell carcinoma (Merkel cell carcinoma) , Kidney cancer or endometrial cancer. In some embodiments, the second therapeutic agent is MPDL3280A and the cancer to be treated is lung cancer (eg, non-small cell lung cancer or small cell lung cancer), urothelial cancer, hepatocellular carcinoma, or breast cancer. In some embodiments, the second therapeutic agent is MEDI4736 and the cancer to be treated is lung cancer (eg, non-small cell lung cancer or small cell lung cancer) or urothelial cancer. In some embodiments, the second therapeutic agent is MSB0010718C and the cancer treated is urothelial carcinoma. In some embodiments, the second therapeutic agent is MSB0010718C and the cancer to be treated is melanoma, lung cancer (such as non-small cell lung cancer), colorectal cancer, kidney cancer, ovarian cancer, pancreatic cancer, gastric cancer, and breast cancer.

Advantageously, the compounds of the present invention and checkpoint inhibitors can be used synergistically to treat cancer. Without wishing to be bound by theory, the synergy between the compound of the present invention and the checkpoint inhibitor can be attributed to the enhanced efficacy of the checkpoint inhibitor related to the down-regulation of Foxp3+ Treg cells induced by BRD9 inhibition.

In some embodiments, the anti-cancer therapy is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. T cells can be modified to express chimeric antigen receptors (CAR). CAR-modified T (CAR-T) cells can be produced by any method known in the art. For example, CAR-T cells can be produced by introducing a suitable expression vector encoding CAR into T cells. Before T cell expansion and genetic modification, a source of T cells is obtained from the individual. T cells can be obtained from many sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, many T cell strains available in the art can be used. In some embodiments, the T cell is an autologous T cell. Whether before or after T cells are genetically modified to express a desired protein (such as CAR), T cells can generally be activated and expanded using methods such as those described in the following: U.S. Patent Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and US Patent Application Publication No. 20060121005.

In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially in either order. The first therapeutic agent can be up to 1 hour before or after the second therapeutic agent, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours , Up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours or up to 1-7 days, 1-14 days, 1-21 days or 1-30 days for immediate administration . Pharmaceutical composition

The pharmaceutical composition described herein is preferably formulated as a pharmaceutical composition in a biologically compatible form suitable for in vivo administration for administration to a human individual.

The compounds described herein can be used as free bases, as salts, solvates, and as prodrugs. All forms are within the methods described herein. According to the method of the present invention, as understood by those skilled in the art, the compound or its salt, solvate or prodrug can be administered to the patient in various forms, depending on the chosen route of administration. The compounds described herein can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, transrectal, patch, pump, intratumoral or transdermal administration, and the pharmaceutical composition accordingly Deployment. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, transnasal, intrapulmonary, intrathecal, transrectal, and surface administration modes. Parenteral administration can be performed by continuous infusion over a selected period of time.

The compounds described herein can be administered orally, for example, using an inert diluent or an absorbable edible carrier, or they can be enclosed in hard or soft shell gelatin capsules, or they can be compressed into tablets, or they can be Directly merge with food. For oral therapeutic administration, the compounds described herein can be combined with excipients and used in the form of ingestible lozenges, buccal lozenges, dragees, capsules, elixirs, suspensions, syrups, and wafers . The compounds described herein can also be administered parenterally. Solutions of the compounds described herein can be prepared in water suitable for mixing with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO and mixtures thereof with or without alcohol and in oil. Under normal storage and use conditions, these preparations may contain preservatives to prevent the growth of microorganisms. The conventional procedures and ingredients for selecting and preparing suitable formulations are described in, for example, Remington's Pharmaceutical Sciences (2012, 22nd edition) and The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for preparing sterile injectable solutions or dispersions for temporary use. In all cases, the form must be sterile and fluid, so that it can be easily administered via a syringe. The composition for nasal administration should be formulated into aerosols, drops, gels and powders. Aerosol formulations usually include a solution or microsuspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually presented in a sterile form in single or multiple doses in a sealed container, the sealed container It can be used in the form of a cartridge or a refill product for the atomization device. Alternatively, the sealed container may be an integrated spray device, such as a single-dose transnasal inhaler or an aerosol sprayer equipped with a metering valve that is intended to be discarded after use. Where the dosage form includes an aerosol dispenser, it will contain a propellant, which may be a compressed gas, such as compressed air, or an organic propellant, such as chlorofluorocarbons. The aerosol dosage form can also take the form of a pump sprayer. Compositions suitable for buccal or sublingual administration include lozenges, lozenges and pastilles, in which the active ingredients are formulated with carriers such as sugar, acacia, tragacanth, gelatin and glycerin. The composition for rectal administration is preferably in the form of a suppository containing a conventional suppository base, such as cocoa butter. The compounds described herein can be administered intratumorally, for example as an intratumor injection. Intratumor injection is directly injected into tumor blood vessels, and is specifically envisaged to be used for discrete, solid, and easily accessible tumors. Local, regional or systemic administration may also be appropriate. The compounds described herein are preferably contacted by administering an injection or multiple injections to the tumor, for example, at about 1 cm intervals. In the case of a surgical operation, the present invention can be used before the operation in order to perform resection of the tumor that is not suitable for operation. When appropriate, continuous administration can also be performed, for example, by implanting a catheter into the tumor or the blood vessel of the tumor.

As shown herein, the compounds described herein can be administered to animals, such as humans, alone or in combination with pharmaceutically acceptable carriers, where the ratio is determined by the solubility and chemical properties of the compound, the chosen route of administration, and standard medicine. Practice decision. dose

The dosage of the compound described herein and/or the composition including the compound described herein may vary depending on various factors, such as the efficacy of the compound; the mode of administration; the age, health and weight of the recipient; and symptoms Nature and extent The frequency of treatment and the type of concurrent treatment (if any); and the clearance rate of the compound in the animal to be treated. Those skilled in the art can determine the appropriate dosage based on the above factors. The compounds described herein can be initially administered in a suitable dose, and the dose can be adjusted as needed depending on the clinical response. Generally speaking, satisfactory results can be obtained when the compounds described herein are administered to humans in daily doses, for example, between 0.05 mg and 3000 mg (measured in solid form). The dosage range includes, for example, between 10-1000 mg (for example, 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

Alternatively, the patient's weight can be used to calculate the dose. For example, the dose of the compound or its pharmaceutical composition administered to the patient may be in the range of 0.1-100 mg/kg. Set

The present invention is also characterized by a kit, which includes (a) a pharmaceutical composition comprising the agent described herein that reduces the level and/or activity of BRD9 in a cell or individual, and (b) a pharmaceutical composition capable of performing one of the methods described herein The package insert of either of the instructions. In some embodiments, the kit includes (a) a pharmaceutical composition comprising an agent described herein that reduces the level and/or activity of BRD9 in a cell or individual, (b) an additional therapeutic agent (e.g., an anticancer agent), And (c) a package insert with instructions for performing any of the methods described herein. Examples Example 1-BRD9 degrading agent depletes BRD9 protein

The following example demonstrates the depletion of BRD9 protein in synovial sarcoma cells treated with BRD9 degrading agent.

Procedure : Use DMSO or BRD9 degrading agent compound 1 (also known as dBRD9, see Remillard et al., Angew. Chem. Int. Ed. Engl. 56(21):5738-5743 (2017); see the structure of compound 1 below ) Treatment, dosage and time point are as indicated.

The whole cell extract was fractionated by SDS-PAGE and transferred to a polyvinylidene fluoride membrane using a transfer device according to the manufacturer's protocol (Bio-Rad). After incubating with TBST containing 5% skim milk (10 mM Tris pH 8.0, 150 mM NaCl, 0.5% Tween 20) for 60 minutes, the membrane was incubated with BRD9 (1:1,000, Bethyl laboratory A303-781A), GAPDH ( 1:5,000, Cell Signaling Technology) and/or MBP (1:1,000, BioRad) antibodies were incubated overnight at 4°C. Wash the membrane three times for 10 minutes and incubate with anti-mouse or anti-rabbit antibodies that bind horseradish peroxidase (HRP, Figure 2-3) or IRDye (Figure 4, 1:20,000, LI-COR) At least 1 hour. The ink dots were washed three times with TBST and developed with the ECL system according to the manufacturer's protocol (Figure 2-3) or scanned on the Odyssey CLx imaging system (Figure 4).

Results : Treatment of SYO1 synovial sarcoma cells with BRD9 degrading agent compound 1 caused a dose-dependent (Figure 1) and time-dependent (Figure 2) exhaustion of BRD9 in the cells. In addition, as shown in Figure 3, the depletion of compound 1 to BRD9 was replicated in a non-synovial sarcoma cell line (293T) and persisted for at least 5 days. Example 2-Inhibition of BRD9 inhibitors and BRD9 degradation agents on the growth of synovial cell lines

The following examples demonstrate that BRD9 degrading agents and inhibitors selectively inhibit the growth of synovial sarcoma cells. program:

Cells were treated with DMSO or BRD9 degradation agent compound 1 at the indicated concentration, and from day 7 to day 14, proliferation was monitored by measuring confluence over time using the IncuCyte live cell analysis system (Figure 4). Renew the growth medium and compounds every 3-4 days.

The cells were seeded into a 12-well plate, and DMSO, 1 μM BRD9 inhibitor, compound 2 (also known as BI-7273, see Martin et al., J Med Chem. 59(10):4462-4475 (2016); see The following structure of compound 2) or 1 μM BRD9 degradation agent compound 1 treatment.

Optimize the number of cells for each cell line. Renew the growth medium and compounds every 3-5 days. On the 11th day, SYO1, Yamato, A549, 293T and HS-SY-II cells were fixed and stained. ASKA cells were fixed and stained on the 23rd day. Incubate with crystal violet solution (0.5 g crystal violet, 27 ml 37% formaldehyde, 100 mL 10X PBS, 10 mL methanol, 863 dH20 to 1L) for 30 minutes, then wash 3 times with water and dry the incubation plate at room temperature for at least Dyeing takes 24 hours. The incubation plate was then scanned on the Odyssey CLx imaging system (Figure 5).

The cells were seeded into 200 μL of complete medium in a 96-well ultra-low cluster plate (Costar, #_7007) and treated with DMSO, Staurosporin or BRD9 degrading agent compound 1 at the indicated dose on the second day (Figure 2C). The medium and compound were changed every 5 days and the cell colony was imaged on the 14th day.

Results: As shown in Figures 4, 5 and 6, treatment of synovial sarcoma cell lines (SYO1, Yamato, HS-SY-II and ASKA) with BRD9 inhibitor compound 2 or BRD9 degrading agent compound 1 caused cell growth inhibition, but It did not cause inhibition of the growth of non-synovial control cancer cell lines (293T, A549, G401). Example 3- Selective inhibition of the growth of synovial cell lines by BRD9 degrading agent and BRD9 binding agent

The following examples demonstrate that BRD9 degrading agents and binding agents selectively inhibit the growth of synovial sarcoma cells.

Procedure: Inoculate cells into 6-well or 12-well plates and daily use BRD9 degrading agent (compound 1), bromodomain BRD9 binding agent (compound 2), E3 ligase binding agent (lenalidomide), DMSO or Staurosporine (positive control for cell killing) was treated at the indicated concentration. Optimize the number of cells for each cell line. Renew the growth medium every 5 days. On day 14, remove the medium, wash the cells with PBS, and stain with 500 μL of 0.005% (w/v) crystal violet solution in 25% (v/v) methanol at room temperature for at least 1 hour. The incubation plate was then scanned on the Odyssey CLx imaging system.

Results: As shown in Figures 7 and 8, treatment of synovial sarcoma cell lines (SYO1, HS-SY-II and ASKA) with compound 1 or compound 2 caused cell growth inhibition, but did not cause non-synovial control cancer cell lines ( Inhibition of the growth of RD, HCT116 and Calu6). Overall, compound 1 showed the most significant growth inhibition among all synovial cell lines. Example 4- Inhibition of cell growth in synovial sarcoma cells

The following examples show that BRD9 degrading agents inhibit cell growth and induce apoptosis in synovial sarcoma cells.

Procedure: SYO1 cells were treated with DMSO, 200 nM or 1 μM BRD9 degradation agent (compound 1) or 200 nM E3 ligase binding agent (lenalidomide) for 8 or 13 days. The compound is updated every 5 days. Use Click-iT™ Plus EdU flow cytometry analysis (Invitrogen) to perform cell cycle analysis. Use Annexin V-FITC Apoptosis Detection Kit (Sigma A9210) to perform apoptosis analysis. Perform analysis according to the manufacturer's plan.

Results: As shown in Figures 9-12, treatment with compound 1 for 8 or 13 days caused a decrease in the number of cells in the S phase of the cell cycle compared with DMSO and lenalidomide. Treatment with compound 1 for 8 days also caused an increase in the number of early and late apoptotic cells compared with the DMSO control. Example 5-SS18-SSX1-BAF composition

The following example shows the identification of BRD9 as a component of the BAF complex containing SS18-SSX.

Procedure: Use lentivirus integration to generate a stable 293T cell line expressing HA-SS18SSX1. The BAF complex containing SS18-SSX1 was subjected to affinity purification and then mass spectrometry analysis revealed the SS18-SSX1 interaction protein.

步驟 1 ：製備 6- 氯 -4- 甲基吡啶 -3- 甲醯胺 ( 中間物 B)

Results: As shown in Figure 13, the BAF complex including the SS18-SSX fusion protein also includes BRD9. For ARID1A (95 peptides), ARID1B (77 peptides), SMARCC1 (69 peptides), SMARCD1 (41 peptides), SMARCD2 (37 peptides), DPF2 (32 peptides), SMARCD3 (26 peptides), ACTL6A (25 peptides), BRD9 (22 peptides), DPF1 isoform 2 (18 peptides), DPF3 (13 peptides) and ACTL6B (6 peptides) identified more than 5 unique peptides. Example 6- Preparation of 4-[6-( azetidin- 1 -yl )-2- methyl- 1 -oxo -2,7 -naphthyridin- 4 -yl ]-2,6 -dimethyl Oxybenzaldehyde ( Intermediate H)

Step 1 : Preparation of 6- chloro- 4 -methylpyridine- 3 -carboxamide ( Intermediate B)

To stirring 6-chloro-4-methylpyridine-3-carboxylic acid (20.00 g, 116.564 mmol, 1.00 equivalent) and NH ₄ Cl (62.35 g, 1.17 mol, 10.00 equivalent) in dichloromethane (DCM; 400 mL) Add DIEA (22.60 g, 174.846 mmol, 3.00 equivalents) to the mixture. After stirring for 5 minutes, HATU (66.48 g, 174.846 mmol, 1.50 equivalents) was added portionwise. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with 1/1 to 3/2 petroleum ether/ethyl acetate (PE/EtOAc) to obtain a yellow solid 6-Chloro-4-methylpyridine-3-carboxamide (18.30 g, 61.3%). LCMS (ESI) m/z: [M+H] ⁺ = 171. Step 2 : Preparation of 6- chloro- N-[(1E)-( dimethylamino ) methylene ]-4 -methylpyridine- 3 -methanamide ( Intermediate C)

A mixture of 6-chloro-4-methylpyridine-3-carboxamide (18.30 g, 107.268 mmol, 1.00 equivalent) and 2-methyltetrahydrofuran (100 mL) stirred at 80°C under a nitrogen atmosphere DMF-DMA (19.17 g, 160.903 mmol, 1.50 equivalents) was added to it, and the mixture was stirred for 1 hour. Then the mixture was cooled and concentrated to give 6-chloro-N-[(1E)-(dimethylamino)methylene]-4-methylpyridine-3-methanamide (26.3 g, 91.3%), which was used without further purification. LCMS (ESI) m/z: [M+H] ⁺ = 226. Step 3 : Preparation of 6- chloro- 2H-2,7 -naphthyridin- 1 -one ( Intermediate D)

To a stirred mixture of 6-chloro-N-[(1E)-(dimethylamino)methylene]-4-methylpyridine-3-carboxamide (26.30 g) in THF (170.00 mL) Add t-BuOK (174.00 mL, 1 mol/L in THF). The resulting solution was stirred at 60°C under a nitrogen atmosphere for 30 minutes. Then the mixture was cooled and concentrated under reduced pressure. The crude solid was washed with saturated NaHCO ₃ solution (100 mL) and collected to give 6-chloro-2H-2,7-naphthyridin-1-one (14.1 g, 67.0%) as a pink solid without further Purify and use directly. LCMS (ESI) m/z: [M+H] ⁺ = 181. Step 4 : Preparation of 6- chloro -2- methyl- 2,7 -naphthyridin- 1 -one ( Intermediate E)

To a stirred mixture of 6-chloro-2H-2, 7-naphthyridin-1-one (14.10 g, 78.077 mmol, 1.00 equivalent) in anhydrous THF (280.00 mL) was added NaH (9.37 g, 234.232 mmol, 3.00 equivalent, 60%). After 10 minutes, MeI (33.25 g, 234.232 mmol, 3.00 equivalents) was added at 0°C, and the mixture was stirred at 0°C for 10 minutes, and then the mixture was stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduced pressure. The crude solid was slurried with water (100 mL), and the solid was filtered and collected to give 6-chloro-2-methyl-2,7-naphthyridin-1-one (14.6 g, 94.1%) as a yellow solid, It was used without further purification. LCMS (ESI) m/z: [M+H] ⁺ = 195. Step 5 : Preparation of 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one ( Intermediate F)

To a stirred mixture of 6-chloro-2-methyl-2,7-naphthyridin-1-one (8.00 g, 41.106 mmol, 1.00 equivalent) in DMF (160.00 mL) was added NBS (8.78 g, 49.327 mmol) , 1.20 equivalents), and the resulting mixture was stirred at 90°C for 2 hours. The reaction mixture was cooled and diluted with DCM (150 mL) and washed with water (3×100 mL). The organic layer was dried and concentrated. The residue was then slurried with EtOAc (20 mL), and the slurry was filtered. The filter cake was washed with EtOAc (20 mL) to give 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one (6.32 g, 55.7%) as a white solid. Use directly after further purification. LCMS (ESI) m/z: [M+H] ⁺ = 273. Step 6 : Preparation of 6-( azetidine- 1 -yl )-4- bromo -2- methyl- 2,7 -naphthyridin- 1 -one ( Intermediate G)

To 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one (5.00 g, 18.281 mmol, 1.00 equivalent) and azetidine hydrochloride (3.2 g, 54.843 mmol, _{3 equivalents) K 2} CO ₃ (12.6 g, 91.404 mmol, 5 equivalents) was added to the solution in DMSO (50.00 mL). The resulting solution was stirred at 130°C for 2 hours. The resulting mixture was cooled and diluted with water (100 mL), and then extracted with EtOAc (3×100 mL). The combined organic layer was washed with saturated NaCl solution (3×50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain 6-(azetidin-1-yl)- as a gray solid 4-Bromo-2-methyl-2,7-naphthyridin-1-one (3.7 g, 68.8%), which was used without further purification. LCMS (ESI) m/z: [M+H] ⁺ = 294. Step 7 : Preparation of 4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethyl Oxybenzaldehyde ( Intermediate H)

步驟 1 ：製備 5- 溴 -2-( 溴甲基 ) 苯甲酸甲酯 ( 中間物 J).

To 6-(azetidin-1-yl)-4-bromo-2-methyl-2,7-naphthyridin-1-one (1.42 g, 4.827 mmol, 1.00 equivalent) and 4-methanyl -3,5-Dimethoxyphenylboronic acid (1.52 g, 7.241 mmol, 1.5 equivalents) in dioxane (16.00 mL) and H ₂ O (4.00 mL) was added Pd(dppf)Cl ₂ ( 353.2 mg, 0.483 mmol, 0.1 equivalent) and Cs ₂ CO ₃ (3.15 g, 9.655 mmol, 2 equivalents), and the resulting solution was stirred at 70° C. for 2 hours. The resulting mixture was cooled and concentrated under reduced pressure. The residue was slurried with water (30 mL) and filtered, and the filter cake was collected. This solid was further slurried with MeOH (30 mL) and filtered. The solid was collected to obtain 4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2 as a gray solid ,6-Dimethoxybenzaldehyde (1.42 g, 77.5%). LCMS (ESI) m/z: [M+H] ⁺ = 380. Example 7- Preparation of 3-[1 -Pendoxy -6-[7-( piperidin- 4 -ylmethyl )-2,7 -diazaspiro [3.5] nonane- 2- yl ]-3H- Isoindol- 2- yl ] piperidine- 2,6 -dione ( Intermediate P)

Step 1 : Preparation of methyl 5- bromo -2-( bromomethyl) benzoate ( Intermediate J).

To a stirred mixture of methyl 5-bromo-2-methylbenzoate (50.00 g, 218.271 mmol, 1.00 equivalent) in CCl ₄ (500.00 mL) was added NBS (38.85 g, 218.271 mmol, 1.00 equivalent) and BPO (5.59 g, 21.827 mmol, 0.10 equivalents). After stirring overnight at 80°C, the mixture was purified by silica gel column chromatography and eluted with PE/EtOAc (50:1) to obtain 5-bromo-2-(bromomethyl)benzene as a yellow oil. Methyl formate (67 g, 74.75%). LCMS (ESI) m/z: [M+H] ⁺ = 307. Step 2 : Preparation of 4-(6- bromo- 1 -oxo -3H- isoindol- 2- yl )-4 -aminomethanylbutyric acid tert-butyl ester ( Intermediate K)

To the stirred methyl 5-bromo-2-(bromomethyl)benzoate (67.00 g, 217.554 mmol, 1.00 equivalent) and (4S)-4-amino-4-aminomethanylbutyrate tert-butyl ester To a mixture of hydrochloride (62.32 g, 261.070 mmol, 1.20 equivalents) in DMF (100.00 mL) was added DIEA (112.47 g, 870.217 mmol, 4 equivalents). After stirring at 80°C overnight, the mixture was concentrated under reduced pressure. Water (200 mL) was added to the residue and stirred at room temperature for 1 hour. The resulting mixture was filtered, water (100 mL) was added to the filter cake and stirred. The precipitated solid was collected by filtration and washed with water (3×30 mL). This produced 4-(6-bromo-1-oxo-3H-isoindol-2-yl)-4-aminomethanylbutyric acid tert-butyl ester (55 g, 60.46%) as an off-white solid. . LCMS (ESI) m/z: [M+H] ⁺ =397. Step 3 : Preparation of 2-[2-[4-( tertiary butoxy )-1 -aminomethanyl- 4 -oxobutyl ]-3 -oxo -1H- isoindole- 5- yl] -2,7-diazaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (intermediate L)

To the stirred 4-(6-bromo-1-oxo-3H-isoindol-2-yl)-4-aminomethanylbutyric acid tert-butyl ester (10.00 g, 25.172 mmol, 1.00 equivalent) and 2,7-diazaspiro[3.5] nonane-7-carboxylic acid tert-butyl ester hydrochloride (8.60 g, 32.723 mmol, 1.30 equivalent) in dioxane (200.00 mL) was added Cs ₂ CO ₃ (24.60 g, 75.516 mmol, 3.00 equivalents) and the third generation RuPhos Palladacycle (2.11 g, 2.517 mmol, 0.10 equivalents). After stirring overnight at 100°C under a nitrogen atmosphere, the resulting mixture was filtered while hot, and the filter cake was washed with 1,4-dioxane (3×50 mL). The filtrate was concentrated under reduced pressure to obtain 2-[2-[4-(tertiary butoxy)-1-aminomethanyl-4-oxobutyl]-3-oxo- as a black solid 1 H -Isoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tertiary butyl ester (21 g, crude). LCMS (ESI) m/z: [M+H] ⁺ = 543. Step 4 : Preparation of 2-[2-(2,6 -dioxopiperidin- 3 -yl )-3 -oxo -1H- isoindol- 5- yl ]-2,7 -diazepine Spiro [3.5] nonane- 7- carboxylic acid tert-butyl ester ( intermediate M)

To the stirring of 2-[2-[(1S)-4-(tertiary butoxy)-1-aminomethanyl-4-oxobutyl]-3-oxo-1 H -isoindyl Dol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (13.68 g, 25.208 mmol, 1.00 equivalent) in THF (100.00 mL) is added to the mixture containing t-BuOK in THF (25.00 mL, 25.000 mmol, 0.99 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 6 with 1 M HCl (aqueous) and then neutralized to pH 7 _{with saturated NaHCO 3 (aqueous).} The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layer was concentrated under reduced pressure. This produces 2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo- 1H -isoindol-5-yl]-2,7 as a yellow solid -Diazaspiro[3.5]nonane-7-t-butyl carboxylate (7.8 g, 59.43%). LCMS (ESI) m/z: [M+H] ⁺ = 469. Step 5 : Preparation of 3-(6-[2,7 -diazaspiro [3.5] nonan- 2- yl ]-1 -oxo -3H- isoindol- 2- yl ) piperidine -2, 6- Diketone ( Intermediate N)

To the stirring of 2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo- 1H -isoindol-5-yl]-2,7-diazepine To a mixture of spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (7.80 g, 16.647 mmol, 1.00 equivalent) in DCM (10.00 mL) was added trifluoroacetic acid (TFA; 5.00 mL). After stirring for 2 hours at room temperature, the resulting mixture was concentrated under vacuum. This produces 3-(6-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo- 3H -isoindol-2-yl) as a pale yellow solid Piperidine-2,6-dione (6 g, 92.93%). LCMS (ESI) m/z: [M+H] ⁺ = 369. Step 6 : Preparation of 4-([2-[2-(2,6 - dioxopiperidin-3 -yl )-3 -oxo -1H- isoindol- 5- yl ]-2,7 - diazaspiro [3.5] nonane-7-yl] methyl) piperidine-1-carboxylic acid tert-butyl ester (intermediate O)

Stir the 3-(6-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo- 3H -isoindol-2-yl)piper at room temperature Pyridin-2,6-dione (4.00 g, 8.685 mmol, 1.00 equivalent, 80%) and tert-butyl 4-methylpiperidine-1-carboxylate (1.48 g, 6.939 mmol, 0.80 equivalent) in DMF ( 20.00 mL) was added NaBH(OAc) ₃ (3.68 g, 17.363 mmol, 2.00 equivalents). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was subjected to reverse phase flash chromatography using the following conditions (column, C18 silica gel; mobile phase, _{water containing CH 3} CN (0.1% FA), 0 to 100% gradient in 40 minutes; detector, UV 254 nm) to purify. This produces 4-([2-[2-(2,6-di-oxopiperidin-3-yl)-3-oxo- 1H -isoindol-5-yl as a dark yellow solid ]-2,7-Diazaspiro[3.5]nonane-7-yl]methyl)piperidine-1-carboxylic acid tert-butyl ester (2.8 g, 51.29%). LCMS (ESI) m/z: [M+H] ⁺ = 566. Step 7 : Preparation of 3-[1 -oxo -6-[7-( piperidin- 4 -ylmethyl )-2,7 -diazaspiro [3.5] nonane- 2- yl ]-3H- Isoindol- 2- yl ] piperidine- 2,6 -dione ( Intermediate P)

To the stirring of 4-([2-[2-(2,6- dilateral oxypiperidin-3-yl)-3-lateral oxy-1 H -isoindol-5-yl]-2,7 -Diazaspiro[3.5]nonane-7-yl]methyl)piperidine-1-carboxylic acid tert-butyl ester (2.80 g, 4.949 mmol, 1.00 equivalent) in DCM (5.00 mL) is added TFA (2.00 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain 3-[1-oxo-6-[7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonane as a yellow solid 2-yl] -3 H - isoindol-2-yl] piperidine-2,6-dione (3.9 g, crude material). LCMS (ESI) m/z: [M+H] ⁺ = 466. Example 8- Preparation of 3-[6-(7-[[1-([4-[6-( azetidin- 1 -yl )-2- methyl- 1 -oxo -2,7- Naphthyridin- 4 -yl ]-2,6 -dimethoxyphenyl ] methyl ) piperidin- 4 -yl ] methyl ]-2,7 -diazaspiro [3.5] nonane- 2- yl )-1 -Panoxy -3H- isoindol- 2- yl ) piperidine- 2,6 -dione TFA salt ( Compound D1 TFA salt )

3-[1-Pendant oxy-6-[7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl]-3H-isoindole -2-yl]piperidine-2,6-dione (4.5 g, 10.52 mmol, 1.00 equivalent) and 4-[6-(azetidin-1-yl)-2-methyl-1-side Oxy-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde (4.0 g, 10.52 mmol, 1.00 equivalent) and titanium(IV) isopropoxide (3.0 g, 10.52 mmol , 1.00 equivalent) in DMSO (100 mL) was stirred at room temperature for 3 hours. Then NaBH(OAc) ₃ (8.92 g, 42.08 mmol, 4.00 equivalents) was added in portions to the above resulting solution, and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (30 mL), and then the solution was filtered. The filter cake was washed with water and acetonitrile. The filtrate was then concentrated in vacuo. The crude product was subjected to reverse phase flash chromatography using the following conditions (column: AQ C18 column, 50 × 250 mm 10 µm; mobile phase A: water (TFA 0.1%), mobile phase B: CAN; flow rate: 100 ml /Min; gradient: 5 B to 25 B in 35 minutes; 254/220 nm) for purification. The pure fraction was evaporated to dryness to obtain 3-[6-(7-[[1-([4-[6-(azetidin-1-yl)-2-methyl-1 as a white solid -Pendant oxy-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]methyl)-2,7-diazaspiro [3.5] Nonan-2-yl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione TFA salt (3.2 g, 32.3%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 10.96 (s, 1H), 9.01 (s, 1H), 7.59 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.72 (s, 2H) ), 6.68 (d, J = 8.1 Hz, 2H), 6.20 (s, 1H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 – 4.13 (m, 2H), 4.06 – 3.95 (m, 4H), 3.80 (s, 6H), 3.57 (s, 4H), 3.47 (s, 5H), 2.97 – 2.75 (m, 3H), 2.70 – 2.55 (m, 1H), 2.44 – 2.16 (m, 7H) , 2.13 – 1.88 (m, 5H), 1.80 – 1.67 (m, 4H), 1.61 (d, J = 12.4 Hz, 2H), 1.53 – 1.33 (m, 1H), 1.13 – 0.94 (m, 2H). LCMS (ESI) m/z: [M+H] ⁺ = 829.55.

The enantiomers of compound D1 were separated by supercritical fluid chromatography on a palm support to produce compound S-D1 and compound R-D1. Example 9- Preparation of Compound D2

Similar to the procedure described in the above examples, compound D2 was prepared using appropriate starting materials.

Compound D2: ¹ H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.02 (d, J = 0.7 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.88 (s, 2H), 6.70 (h, J = 2.4 Hz, 2H), 6.24 (d, J = 6.0 Hz, 1H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.41 – 4.14 (m, 4H), 4.04 (t, J = 7.4 Hz, 4H), 3.91 (s, 1H), 3.70 (d, J = 22.5 Hz, 4H), 3.50 (s, 3H), 3.45 (s, 1H), 3.22 (s, 1H), 3.14 – 2.82 (m, 6H), 2.60 (d, J = 16.2 Hz, 1H), 2.55 (s, 2H), 2.44 – 2.28 (m, 3H) , 2.18 – 2.05 (m, 3H), 1.97 (t, J = 13.9 Hz, 5H), 1.51 (q, J = 12.2, 11.1 Hz, 2H). LCMS (ESI) m/z: [M+H] ⁺ = 835.45. Example 10-SYO1 BRD9 NanoLuc degradation analysis

This example demonstrates the ability of the compound of the present disclosure to degrade Nanoluciferase-BRD9 fusion protein in a cell-based degradation analysis.

Procedure: Generate a stable SYO-1 cell line expressing 3xFLAG-NLuc-BRD9. On day 0, the cells were seeded in 30 μL of medium in each well of a 384-well cell culture plate. The seeding density is 8000 cells/well. On day 1, the cells were treated with 30 nL DMSO or 30 nL of the compound diluted 3 times in DMSO (10 points in duplicate, 1 μM as the final highest dose). The incubation plate was then incubated in a standard tissue culture incubator for 6 hours and equilibrated at room temperature for 15 minutes. The Nanoluciferase activity was measured by adding 15 μL of freshly prepared Nano-Glo Luciferase Assay Reagent (Promega N1130), shaking the incubation plate for 10 minutes and reading the bioluminescence using an EnVision reader.

Result : Use the following formula to calculate the% inhibition:% inhibition = 100 × (Lum _HC -Lum _sample ) / (Lum _{HC- Lum LC} ). Cells treated with DMSO were used as high control (HC) and cells treated with 1 μM of a known BRD9 degrading agent standard were used as low control (LC). The data was fitted into a four-parameter nonlinear curve fitting to calculate the IC ₅₀ (μM) value, as shown in Table 2. As shown in the results of Table 2, a number of compounds of the present disclosure exhibit degradation BRD9 ₅₀ values of IC <1 μM, indicating that this level is used as the reducing BRD9 and / or activity of their potential for the treatment of disorders related to the BRD9. Table 2. SYO1 BRD9-NanoLuc degradation Compound number SYO1 BRD9-NanoLuc degradation IC ₅₀ (nM) D1 0.13 D2 0.18 Example 11-BRD9 degradation inhibits synovial sarcoma tumor growth in vivo

Method: NOD SCID mice (Beijing Anikeeper Biotech, Beijing) were subcutaneously inoculated into the right waist fossa with SYO-1 human biphasic synovial sarcoma tumor cells (5×106) in 100 μL with 10% fetal bovine serum (FBS) Single cell suspension in Dulbecco's Modified Eagle Medium (DMEM). When the average tumor size reached about 117 mm ³ , the mice were randomized to the control group [10% dimethyl sulfoxide (DMSO), 40% polyethylene glycol (PEG400) and 50% water] or treatment group D1. The mice were dosed daily via the intraperitoneal (ip) route over the course of 3 weeks. All dose volumes are adjusted according to mg/kg with body weight.

Results: As shown in Figure 14, treatment with 1 mg/kg compound D1 caused tumor growth inhibition. Based on the observed weight change %, all treatments were well tolerated. Example 12- Compound D1 causes BRD9 degradation in synovial sarcoma tumors in vivo

Method: The mice were treated with 1 mg/kg D1 ip for 4 weeks. The mice were then euthanized, and tumors were collected at 8 hours, 72 hours, and 168 hours after the last dose. Tumors were lysed with 1x RIPA lysis buffer (Boston BioProducts, BP-115D) with protease and phosphatase protein inhibitors (Roche Applied Science # 04906837001 and 05892791001). The same amount of lysate (30 μg) was loaded into a 4-12% Bis-Tris Midi protein gel in 1X MOPS buffer; the sample was run at 120 V for 120 minutes. The protein was transferred to a membrane with TransBlot at 250 mA for 150 minutes, and then the membrane was blocked with Odyssey blocking buffer for 1 hour at room temperature. The membrane was hybridized with the primary antibody in the cold room overnight. Images were acquired using Li-COR imaging system (Li-COR Biotechnology, Lincoln, Nebraska).

Table 3 shows the detection antibody information. table 3 antibody supplier Catalog number Species dilution BRD9 Bethyl, (Montgomery, TX) A303-781A rabbit 1:1000 GAPDH CST, (Danvers, MA) 97166 Mouse 1:2000

Results : As shown in Figure 15, treatment with 1 mg/kg of compound D1 caused complete degradation of the BRD9 target until 168 hours after administration. Example 13 -Effect of Compound S-D1 and R-D1 on Synovial Sarcoma Cells

Method . Spread the synovial sarcoma cells in a 6-well plate at 500-100k cells/well and use continuous concentrations of BRD9 degradation agent (10 nM maximum concentration, 1:3 dilution) at 37°C at two time points the next day )deal with. The cells were then harvested, washed with cold PBS, and frozen into cell pellets at -80°C. The lysate was prepared by resuspending the thawed agglomerates in 1x RIPA dissolution and extraction buffer (Thermo Fisher, catalog number 89900), which had an EDTA-free 1x Halt™ protease and phosphatase inhibitor cocktail ( Thermo Fisher, catalog number 78441) and Pierce™ cytolysis universal nuclease 25ku (Thermo Fisher, catalog number 88700) diluted 1:1000. The lysate was incubated on ice for 10 minutes, and then centrifuged at maximum speed (15,000 rpm) for 10 minutes at 4°C. Then use BCA protein quantitative analysis to analyze the total protein of the sample, and use lysis buffer and 1x NuPAGE™ LDS sample buffer (4X) (Thermo Fisher, catalog number NP0007) and 1x DTT (Cell Signaling Technologies) from 30X stock solution , Catalog number 14265S) diluted to 1 μg/μL. Load the sample with 20-25 ug total protein into 4-12% Bis-Tris Mini-Gel with 1x MES operating buffer and run at 150V for 45 minutes. Use the Trans-Blot® Turbo™ transfer system (semi-dry) to transfer the gel to the nitrocellulose ink spot at 25V for 10 minutes (high MW setting). The ink spots were blocked in TBST containing 5% milk for 1 hour and BRD9 antibody (SYO1, Bethyl Labs, catalog number A303-781A, 1:750; and ASKA, Cell Signaling Technologies, catalog number 71232S) and β-muscle were used The kinesin antibody (Cell Signaling Technologies, catalog number 3700, 1:2000) was probed at 4°C overnight. The next day, the ink dots were washed 3 times in TBST and 1:5000 IRDye® 680LT goat anti-rabbit IgG secondary antibody (LiCOR, catalog number 926- 68021) and 1:10000 IRDye® 800CW goat anti-mouse IgG secondary antibody (LiCOR, catalog number 926-32210) for 1 hour. The ink dots were washed 3 times in TBST and scanned with a LiCOR Odyssey® CLx imaging system at 700 nM and 800 nM wavelengths. Use the same analysis program included in the same machine to quantify Western ink dot signals. BRD9 signaling was quantified by normalization relative to β-actin signal, and all samples were normalized relative to DMSO set to 100% signal.

To assess the interconversion between enantiomer 1 and enantiomer 2 in the cell culture medium, the following test was performed. Add enantiomer 1 and enantiomer 2 (each 40 μM in DMSO) to the cell culture medium (DMEM + Glutamax + 10% FBS) at a final concentration of 0.2 μM and keep at 37°C and 5% CO ₂ Incubate in duplicate in one format. At the designated time point, an aliquot (50 μL) was obtained and processed by adding 150 μL of acetonitrile containing 0.1% formic acid and an internal standard for LC/MS-MS analysis. The peak area of enantiomer 1 and enantiomer 2 of each sample was determined using the specific analysis method of the palm. The results are summarized in the following 5 tables.

Results . To evaluate the BRD9 degradation activity of the two enantiomers, two synovial sarcoma cell lines (SYO-1 and ASKA) were used for degradation agent treatment and subsequent Western blotting experiments. Significantly more effective BRD9 degradation activity was observed under enantiomer 2, wherein compared with 2.8 nM of enantiomer 1 in SYO-1 for 1 hour, the fitted DC ₅₀ value 0.092 nM (Figures 16, 17 and 18 and Table 4). For enantiomer 2, at 30 minutes, ASKA cells have a more significant difference with a DC ₅₀ of 0.34 nM, but for enantiomer 1, at the same time point, up to 10 μM, the activity is indistinguishable ( Figures 20, 21 and 22 and Table 4). In ASKA, the difference was reduced to about 32-fold at 2 hours, where the fitted DC ₅₀ values of enantiomer 1 and enantiomer 2 were 0.38 nM and 0.012 nM, respectively (Table 4). In SYO1. By 6 hours, the difference was further reduced to approximately 3 times. In the degradation of BRD9, enantiomer 2 is slightly better than its racemic parent compound D1, but is generally equivalent under the same research conditions (Figures 16 and 17). For all three compounds, the BRD9 degradation activity became highly similar at 24 hours (Figure 19). In conclusion, in the two synovial sarcoma cell lines, enantiomer 2 was more effective at degrading endogenous BRD9 protein, while enantiomer 1 was basically inactive or had a greatly reduced degradation efficiency. However, the difference in efficacy decreased over time and basically disappeared by 24 hours. Table 4. Cell line Fitted DC ₅₀ (nM) Enantiomer 1 Enantiomer 2 ASKA 0.5 hour ＞10 0.34 SYO-1 1 hour 2.8 0.092 ASKA 2 hours 0.38 0.012 SYO-1 6 hours 0.066 0.023

Report the epimerization of the palmar center in thalidomide or other IMiD drugs and their derivatives. Under physical or neutral pH conditions, the acidic hydrogen in the palmar center may be disturbed. In order to study the relative stability under the cell analysis conditions of these degradants, a time course study of enantiomer 1 and enantiomer 2 was performed in the cell culture medium at 37°C. At time 0 or 0.5 hours, Enantiomer 2 was not detected in the Enantiomer 1 sample. However, at subsequent time points, a large amount of enantiomer 2 was detected, accounting for 12% and 30% of the total at 2 hours and 6 hours respectively (Table 5). Similarly, enantiomer 2 was converted to enantiomer 1 over time, and at 6 hours, its effective concentration was reduced to 63% (Table 5). These data indicate that the rate of epimerization is relatively fast under cell analysis conditions, and that the time-dependent BRD9 degradation activity of enantiomer 1 may be caused by the converted enantiomer 2. In general, these data indicate that Enantiomer 2 is the active enantiomer that degrades BRD9 in cells. table 5. Time (hour) Enantiomer 1 administration Enantiomer 2 administration The average peak area ratio of enantiomer 2 compared to the peak area ratio of enantiomer 1 Enantiomers 2% The average peak area ratio of enantiomer 1 compared to the peak area ratio of enantiomer 2 Enantiomers 2% 0 0.0 0.0 0.01 99 0.5 0.0 0.0 0.06 95 2 0.13 12 0.22 82 6 0.43 30 0.60 63 Example 14 -Effect of Compound S-D1 and R-D1 on Synovial Sarcoma Cells

Method . SYO-1 tumor cells were adherent cells in vitro and maintained in an atmosphere of air containing 5% CO2 at 37°C in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum. The cells grown in the exponential growth phase were harvested and counted for tumor inoculation. BALB/c nude mice (Shanghai Lingchang biological science) were subcutaneously inoculated into 0.1 mL of phosphate buffered saline (PBS) (5×10 ⁶ ) in the right lumbar fossa. When the average tumor size reached 499 mm ³ , treatment was started on the 19th day after tumor inoculation (described in the table below). Processing information: antibody Number of mice Vehicle control, sulfobutyl ether-β-cyclodextrin (SBECD), single dose, 10 ul/g 3 Racemic D1, 0.5 mg/kg iv, single dose, 10 ul/g (20%SBECD) 12 Enantiomer 1, 0.25 mg/kg iv, single dose, 10 ul/g (20%SBECD) 18 Enantiomer 2, 0.25 mg/kg iv, single dose, 10 ul/g (20%SBECD) 18 Enantiomer 2, 1 mg/kg iv, single dose, 10 ul/g (20%SBECD) 18

Mice were treated with 1 mg/kg racemic D1 ip for 4 weeks, the mice were euthanized, and tumors were collected 1 hour, 4 hours, 8 hours, 24 hours, 48 hours, and 72 hours after the last dose. Tumors were lysed with 1x RIPA lysis buffer (Boston BioProducts, BP-115D) with protease and phosphatase protein inhibitors (Roche Applied Science # 04906837001 and 05892791001). The same amount of lysate (30 μg) was loaded into a 4-12% Bis-Tris Midi protein gel in 1X MOPS buffer; the sample was run at 120 V for 120 minutes. The protein was transferred to a membrane with TransBlot (NC) at 250 mA for 150 minutes, and then the membrane was blocked with Odyssey blocking buffer for 1 hour at room temperature. The membrane was hybridized with the primary antibody in the cold room overnight. Use Li-COR imaging system (Li-COR Biotechnology, Lincoln, Nebraska) to obtain image detection antibody information: antibody supplier Catalog number Species dilution BRD9 Bethyl, (Montgomery, TX) A303-781A rabbit 1:1000 GAPDH CST, (Danvers, MA) 97166 Mouse 1:2000

Results . The pharmacodynamic activity of enantiomer 1, enantiomer 2 and racemic compound D1 was evaluated in the SYO-1 xenograft model. Enantiomer 2 demonstrated significant activity, as assessed by the BRD9 protein level using Western blot analysis, Figure 23. Enantiomer 2 degraded BRD9 up to 72 hours after a single dose. Enantiomer 1 is inactive and does not degrade BRD9 protein. These results indicate that Enantiomer 2 is as effective as racemic compound D1. Other embodiments

All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety. The degree of citation is as if specifically and individually instructed each individual publication, patent or patent application to be cited. The way is integrated into the general. Where it is found that the terms in this application are defined differently in the documents incorporated herein by reference, the definitions provided herein will serve as the definitions of the terms.

Under the circumstance that the present invention has been described in conjunction with its specific embodiments, it should be understood that the present invention can be further modified and this application is intended to cover any variants, uses or changes of the present invention, and such variants, uses or changes generally follow The principle of the present invention includes deviations from the present disclosure that are known or customary in the field to which the present invention belongs, and can be applied to the basic features set forth above, and are within the scope of the patent application.

Other embodiments are within the scope of patent application.

Figure 1 is an image showing the dose-dependent depletion of BRD9 levels in a synovial sarcoma cell line (SYO1) in the presence of a BRD9 degrading agent. Figure 2 is an image showing the continuous inhibition of BRD9 levels in the synovial sarcoma cell line (SYO1) in the presence of a BRD9 degrading agent within 72 hours. Figure 3 is an image showing the continuous inhibition of BRD9 levels in the presence of a BRD9 degrading agent in two cell lines (293T and SYO1) within 5 days. Figure 4 is an image showing the continuous inhibition of BRD9 levels in synovial sarcoma cell lines (SYO1 and Yamato) in the presence of BRD9 degrading agents for 7 days compared with the levels in cells treated with CRISPR reagents. Fig. 5 is an image showing the effect on cell growth of six cell lines (SYO1, Yamato, A549, HS-SY-II, ASKA and 293T) in the presence of a BRD9 degrading agent and a BRD9 inhibitor. Figure 6 is an image showing the effect of the BRD9 degrading agent on the cell growth of two cell lines (SYO1 and G401). Fig. 7 is an image showing the effect on cell growth of three synovial sarcoma cell lines (SYO1, HS-SY-II and ASKA) in the presence of BRD9 degrading agent, BRD9 binding agent and E3 ligase binding agent. Fig. 8 is an image showing the effect on cell growth of three non-synovial sarcoma cell lines (RD, HCT116 and Calu6) in the presence of BRD9 degrading agent, BRD9 binding agent and E3 ligase binding agent. Figure 9 is a graph showing the percentage of SYO1 in multiple cell cycle stages after treatment with DMSO, 200 nM compound 1 or 1 μM compound 1 for 8 or 13 days. Figure 10 is a series of contour plots showing the percentage of SYO1 cells in multiple cell cycle stages after treatment with DMSO, 200 nM Compound 1, 1 μM Compound 1, or 200 nM lenalidomide for 8 days. The values corresponding to each contour map are shown in the table below. Figure 11 is a series of contour plots showing the percentage of SYO1 cells in various cell cycle stages after treatment with DMSO, 200 nM Compound 1, 1 μM Compound 1, or 200 nM Lenalidomide for 13 days. The values corresponding to each contour map are shown in the table below. Figure 12 is a series of contour plots showing the percentage of early and late apoptotic SYO1 cells after 8 days of treatment with DMSO, 200 nM Compound 1, 1 μM Compound 1, or 200 nM Lenalidomide. The values corresponding to each contour map are shown in the table below. Figure 13 is a diagram showing the proteins present in the BAF complex including the SS18-SSX fusion protein. Figure 14 is a graph showing the efficacy of Compound D1 in a SOY-1 xenograft mouse model. Treatment with compound D1 caused tumor growth inhibition. Figure 15 is an image showing the Western blot method of BRD9 detection in the control group and the treatment group (Compound D1). Treatment with compound D1 caused BRD9 inhibition. Figure 16 is an image showing the detection of BRD9 in SYO-1 cells treated with DMSO, enantiomer 1 or racemic compound D1 for 1 hour or 6 hours by the Western blot method. Figure 17 is an image showing the detection of BRD9 in SYO-1 cells treated with DMSO, enantiomer 2 or racemic compound D1 for 1 hour or 6 hours by the Western blot method. FIG. 18 is a graph showing a dose response curve fitted to the BRD9 bright band intensity data points from the western blot image shown in FIGS. 16 and 17. Figure 19 is an image showing the detection of BRD9 in SYO-1 cells treated with enantiomer 1, enantiomer 2 or racemic compound D1 for 24 hours by the Western blot method. Figure 20 is an image showing the Western blot method of BRD9 detection in ASKA cell controls and ASKA cells treated with enantiomer 1 or racemic compound D1 for 0.5 hours or 2 hours. Figure 21 is an image showing the Western blot method of BRD9 detection in ASKA cell controls and ASKA cells treated with enantiomer 2 or racemic compound D1 for 0.5 hours or 2 hours. FIG. 22 is a graph showing a dose response curve fitted to the BRD9 bright band intensity data points from the western blot image shown in FIGS. 20 and 21. FIG. Figure 23 shows a series of images of the Western blot method detected by BRD9 in the SYO-1 Zenograft model treated with enantiomer 1, enantiomer 2 or racemic compound D1. Figure 24 is a bar graph quantifying the changes in the BRD9 level observed in the Western ink dot method shown in Figure 23.

Claims (31)

A compound having the following structure:

Compound D1 , or

Compound D2 , or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound has the following structure:

Compound D1 , or a pharmaceutically acceptable salt thereof. The compound of claim 1 or 2, wherein the compound has the following structure:

Compound S-D1 , or a pharmaceutically acceptable salt thereof. The compound of claim 1 or 2, wherein the compound has the following structure:

Compound R-D1 , or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound having the following structure:

Compound D1 , or

Compound D2 , or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises a compound having the following structure:

, Compound D1 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises a compound having the following structure:

, Compound S-D1 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises a compound having the following structure:

, Compound R-D1 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients. A method for inhibiting the level of BRD9 in a cell, the method comprising combining the cell with an effective amount of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or any one of claims 5 to 8 One item of medical composition contact. A method for inhibiting the activity of BRD9 in a cell, the method comprising combining the cell with an effective amount of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or any one of claims 5 to 8 One item of medical composition contact. The method of claim 9 or 10, wherein the cell is a cancer cell. The method of claim 10, wherein the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanin Tumor, colorectal cancer, sarcoma, non-small cell lung cancer, gastric cancer or breast cancer. The method of claim 12, wherein the cancer is a sarcoma. The method of claim 13, wherein the sarcoma is soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, acinar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, Pro-fibroproliferative small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma (Kaposi sarcoma), liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, Myxofibrosarcoma or low-grade rhabdomyosarcoma. The method of claim 14, wherein the sarcoma is synovial sarcoma. The method of claim 14, wherein the sarcoma is rhabdomyosarcoma. A method for treating a BAF complex-related disorder in an individual in need, the method comprising administering to the individual an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or as required The pharmaceutical composition of any one of items 5 to 8. A method for treating an SS18-SSX fusion protein-related disorder in an individual in need thereof, the method comprising administering to the individual an effective amount of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or The pharmaceutical composition according to any one of claims 5 to 8. A method for treating a BRD9-related disorder in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or as claimed in claim 5 The pharmaceutical composition of any one of to 8. The method according to any one of claims 17 to 19, wherein the disorder is cancer. A method for treating cancer in an individual in need, the method comprising administering to the individual an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or as claimed in claims 5 to 8 Any one of the pharmaceutical compositions. The method of claim 20 or 21, wherein the cancer is malignant rhabdoid tumor, CD8+ T cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma , Melanoma, colorectal cancer, sarcoma, non-small cell lung cancer, gastric cancer or breast cancer. The method of claim 22, wherein the cancer is a sarcoma. The method of claim 23, wherein the sarcoma is soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, acinar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, and fibrotic tissue proliferation Small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi’s sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxofibrosarcoma, or low-grade rhabdomyosarcoma . The method of claim 24, wherein the sarcoma is synovial sarcoma. The method of claim 24, wherein the sarcoma is rhabdomyosarcoma. The method according to any one of claims 17 to 19, wherein the disease is infection. A method for treating an infection in an individual in need, the method comprising administering to the individual an effective amount of a compound as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or as claimed in claims 5 to 8 Any one of the pharmaceutical compositions. Such as the method of claim 27 or 28, wherein the infection is a virus infection. Such as the method of claim 29, wherein the viral infection is Retroviridae, Hepadnaviridae, Flaviviridae, Adenoviridae, Herpesviridae ), Papillomaviridae, Parvoviridae, Polyomaviridae, Paramyxoviridae or Togaviridae. The method of claim 29 or 30, wherein the viral infection is Coffin Siris, neurofibromas or multiple meningioma.

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